Prevalence of the apolipoprotein E ε4 allele in amyloid ß positive subjects across the spectrum of Alzheimer's disease.

INTRODUCTION: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid ß (Aß) pathology. METHODS: We included 3451 Aß+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location. RESULTS: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aß+ cognitively normal and Aß+ mild cognitive impairment (P < .05) but not in Aß+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education. DISCUSSION: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aß pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.

Alteration of Neurotrophic Factors After Transplantation of Bone Marrow Derived Lin-ve Stem Cell in NMDA-Induced Mouse Model of Retinal Degeneration.

Retinal ganglion cell layer (RGCs) is one of the important layers of retina, depleted in Glaucoma. Loss of RGC neurons is a major cellular mechanism involved in its pathogenesis resulting in severe vision loss. Stem cell therapy has emerged as a potential strategy to arrest the apoptotic loss of RGCs and also replace the degenerative cells in damaged retina. Here, we have investigated the incorporation and survival of mouse bone marrow derived Lin-ve stem cells in N-methyl-d-aspartate (NMDA)-induced mouse model of retinal degeneration. Two days after intravitreal injection of NMDA (100 mM) showed significant decrease in ganglion cell number and increase in TUNEL positive apoptotic cells in retinal layers. The injury was further characterized by immunohistochemical expression of Brn3b, GFAP, Bcl2, pCREB, CNTF, GDNF, and BDNF in retinal layers. Lin-ve cells (100,000 dose) were intravitreally transplanted after 2 days of injury and evaluated after 7, 14, and 21 days of transplantation. Transplanted cells were found to have migrated from intravitreal space and incorporated into injured retina at 7, 14, and 21 days post-transplantation. At 21 days Brn3b, CNTF, and BDNF expression was found to be upregulated whereas GDNF was downregulated when compared to respective injury time points. Molecular data showed decrease in the expression of Brn3b, BDNF, CNTF, and GDNF post transplantation when compared with injury groups. This study reveals that Lin-ve stem cells may exert neuroprotective effect in damaged retina mediated by participation of neurotrophic factors induced by stem cell transplantation at the site of injury. J. Cell. Biochem. 118: 1699-1711, 2017. © 2016 Wiley Periodicals, Inc.

Evaluation of practice effect on neuropsychological measures among persons with and without HIV infection in northern India.

An evaluation of the effects of HIV infection on neurocognition over time is important for understanding disease progression. Changes in cognitive function can be evaluated longitudinally by using neuropsychological testing at repeated intervals. The assessment of change over time, however, is complicated by the potentially confounding influence of learning on repeated test administrations, often referred to as practice effect. In this study, we present data on testing of persons with or without HIV infection on a battery administered at study baseline and repeated 1 year later. Results suggest that practice effects may be diminished in persons with HIV infection compared to without it. This appears to be true even among those with relatively intact immune functioning as measured by CD4 count.

Transplantation of lineage-negative stem cells in pterygopalatine artery ligation induced retinal ischemia-reperfusion injury in mice.

Retinal ischemia is a condition associated with retinal degenerative diseases such as glaucoma, diabetic retinopathy, and other optic neuropathies, leading to visual impairment and blindness worldwide. Currently, there is no therapy available for ischemic retinopathies. Therefore, the aim of this study was to test a murine model of pterygopalatine artery ligation-induced retinal injury for transplantation of mouse bone marrow-derived lineage-negative (lin-ve) stem cells. The mouse external carotid artery and pterygopalatine artery were ligated for 3.5 h followed by reperfusion. The model was validated through fundus fluorescein angiography, laser Doppler and FITC dextran perfusion in whole-mounts. Lin-ve stem cells isolated from mouse bone marrow were transplanted through tail-vein, which showed migration to retina leading to decrease in GFAP expression. The neurotrophic factors such as BDNF and FGF2 showed enhanced expression in the retina. The functional analysis with electroretinogram did not demonstrate any significant changes before or after injury or stem cell transplantation. This study shows a neuroprotective potential in lin-ve stem cells in the retinal ischemia induced by pterygopalatine artery ligation and presents a practical model for validating therapies for ischemic disorders of the retina in future.

Temporal Trends in Intravenous Thrombolysis in Acute Ischemic Stroke: Experience from a Tertiary Care Center in India.

BACKGROUND: Acute ischemic stroke (AIS) is a time-dependent treatable cause of morbidity and mortality. Despite the increasing stroke incidence in developing countries, parallel increasing stroke thrombolysis rates have not been documented. AIM: This study aims to determine trends in patient characteristics and rates of recombinant tissue plasminogen activator (rtPA) use in AIS patients in a tertiary care center in northern India. METHODS: All AIS patients presenting within 8 hours of symptoms onset from January 2011 to December 2015 were enrolled and analyzed. RESULTS: A total of 867 AIS patients presented within 8 hours of symptoms onset. Out of 593 eligible patients, 189 (31.87%) underwent intravenous thrombolysis (IVT) with rtPA within 4.5 hours of the window period. Patients (undergoing) IVT had onset-to-door times of 2 hours or less (23.81%), 2-3 hours (33.86%), and 3.0-4.5 hours (42.33%). IVT rates in 2 hours or less of symptom onset increased from 22% to 25% and IVT rates in 2-3 hours increased from 38.9% to 43.8%. Door-to-computerized tomographic time (median 27 versus 11 minutes, P = .0001) and door-to-needle time (median 83 versus 67 minutes, P = .011) improved, with a significant improvement of computerized tomography imaging time within 25 minutes of arrival (from 50% to 78.4%, P = .014). Post-IVT symptomatic hemorrhage was noted in 5 patients (2.65%). The median National Institutes of Health Stroke Scale score at presentation was 11, whereas a favorable modified Rankin Scale score (0-1) at 3 months was seen in 39.68%. CONCLUSIONS: Encouraging trends in IVT over the years may be indicative of increasing community awareness of stroke and improving quality of stroke care in developing countries such as India.

Effect of Vitamin D and calcium supplementation on ischaemic stroke outcome: a randomised controlled open-label trial.

BACKGROUND AND AIMS: Vitamin D deficiency is a common problem in stroke survivors. Observational studies have reported an association of low vitamin D levels with greater stroke severity, poststroke mortality and functional disability. Randomised clinical trials are lacking. We sought to assess the effect of calcium and vitamin D supplementation in ischaemic stroke survivors with vitamin D deficiency/insufficiency on disability/mortality outcomes. METHODS: In this randomised controlled open-label trial, 73 patients of acute ischaemic stroke were screened for serum 25 hydroxy Vitamin D (25(OH)D) levels. A total of 53 patients with baseline 25(OH)D <75 nmol/L were randomised into two arms. One received vitamin D and calcium supplementation along with usual care (n=25) and the other received usual care alone (n=28). Primary outcome was the proportion of patients achieving a good outcome [modified Rankin Scale score 0-2] at 6 months and all cause mortality at 6 months. RESULTS: The age (mean±SD) of participants was 60.4±11.3 years, 69.8% were males. The proportion of patients achieving good outcome was higher in the intervention arm (Adjusted OR 1.9, 95% CI 0.6-6.4; P=.31). The survival probability was greater in the intervention arm (83.8%, CI 62.4-93.6) as compared with the control arm (59.5%, CI 38.8-75.2; P=.049) with adjusted Hazard ratio (HR) of 0.26 (95% CI 0.08-0.9; P=.03). CONCLUSIONS: This is the first randomised controlled study assessing the effect of vitamin D and calcium supplementation on ischaemic stroke outcomes and points towards a potential benefit. Findings need to be validated by a larger trial.

Neuropsychological test performance among healthy persons in northern India: development of normative data.

Accurate identification of neurocognitive impairment associated with HIV infection (and other CNS-involved conditions) is dependent upon utilization of appropriate normative neuropsychological test performance data from healthy individuals with a similar background, culture, and characteristics of the target individual or group to be tested. In India, regional differences in language, culture, and availability of resources can significantly affect performance on neuropsychological testing. This study developed age- and education-adjusted normative data for commonly used neuropsychological test scores for use in northern India.

Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial.

BACKGROUND AND PURPOSE: Pilot studies have suggested benefit from intravenous administration of bone marrow mononuclear stem cells (BMSCs) in stroke. We explored the efficacy and safety of autologous BMSCs in subacute ischemic stroke. METHODS: This was a phase II, multicenter, parallel group, randomized trial with blinded outcome assessment that included 120 patients. Patients with subacute ischemic stroke were randomly assigned to the arm that received intravenous infusion of autologous BMSCs or to control arm. Coprimary clinical efficacy outcomes were Barthel Index score and modified Rankin scale at day 180. Secondary outcomes were change in infarct volume, National Institute of Health Stroke Scale (NIHSS) at day 90 and 180. Main safety outcomes were adverse events, any new area of (18)fluorodeoxyglucose positron emission tomography uptake in any body part over 365 days. RESULTS: Fifty-eight patients received a mean of 280.75 million BMSCs at median of 18.5 days after stroke onset. There was no significant difference between BMSCs arm and control arm in the Barthel Index score (63.1 versus 63.6; P=0.92), modified Rankin scale shift analysis (P=0.53) or score >3 (47.5% versus 49.2%; P=0.85), NIHSS score (6.3 versus 7.0; P=0.53), change in infarct volume (-11.1 versus -7.36; P=0.63) at day 180. Adverse events were also similar in the 2 arms, and no patient showed any new area of (18)fluorodeoxyglucose uptake. CONCLUSIONS: With the methods used, results of this hitherto first randomized controlled trial indicate that intravenous infusion of BMSCs is safe, but there is no beneficial effect of treatment on stroke outcome. CLINICAL TRIAL REGISTRATION: URLs: http://ctri.nic.in/Clinicaltrials and http://www.clinicaltrials.gov. Unique identifiers: CTRI-ROVCTRI/2008/091/0004 and NCT0150177.

Does toll-like receptor-3 (TLR-3) have any role in Indian AMD phenotype?

Age-related macular degeneration (AMD) is a devastating disease that results in irreversible central vision loss. TLRs signaling pathway has been found to play an important role in AMD pathogenesis as evidenced by several studies. The objective of the study was to determine the single nucleotide polymorphism (SNP) changes in TLR3 in North Indian AMD patients. We recruited 176 patients comprising 115 AMD patients and 61 controls. Real time PCR was used to evaluate the SNP changes at rs3775291 locus. Pearson's χ(2) test was used evaluate association between various groups. No significant association in genotype and allele frequency was found in AMD patients as compared to control. The results suggest that AMD pathology in North Indian AMD patients is not affected by TLR3 signaling but it could be influenced by other genetic or environmental factors unique to North India.

TNF-α promoter polymorphism: a factor contributing to the different immunological and clinical phenotypes in Japanese encephalitis.

BACKGROUND: More than three billion populations are living under the threat of Japanese encephalitis in South East Asian (SEA) countries including India. The pathogenesis of this disease is not clearly understood and is probably attributed to genomic variations in viral strains as well as the host genetic makeup. The present study is to determine the role of polymorphism of TNF-alpha promoter regions at positions -238G/A, -308G/A, -857C/T and -863C/A in the severity of Japanese encephalitis patients. METHODS: Total of 142 patients including 66 encephalitis case (IgM/RT-PCR positive), 16 fever cases (IgM positive) without encephalitis and 60 apparently healthy individuals (IgG positive) were included in the study. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) using site specific restriction enzymes were implemented for polymorphism study of TNF alpha promoter. RESULTS: Following the analysis of the digestion patterns of four polymorphic sites of the TNF-alpha promoter region, a significant association was observed between the allele -308A and -863C with the patients of Japanese encephalitis. CONCLUSIONS: TNF-alpha 308 G/A has been shown to be associated with elevated TNF-alpha transcriptional activity. On the other hand, polymorphism at position -863C/A in the promoter region has been reported to be associated with reduced TNF-alpha promoter activity and lower plasma TNF levels. As per the literature search, this is the first study to identify the role of TNF-alpha promoter in JE infection. Our results show that subjects with -308A and -863C alleles are more vulnerable to the severe form of JE infection.

HIV infection presenting as cerebral venous sinus thrombosis.

Risk of cerebrovascular disease is increased in patients with HIV infection; however, cerebral venous sinus thrombosis is not commonly reported in this condition. We report a case of young man with intracranial hemorrhage whose radiologic investigations revealed thrombosis of the left transverse and sigmoid sinuses extending into the left internal jugular vein. On further investigations, he was found to be positive for HIV-1, and his procoagulant workup showed protein S deficiency. He was started on anticoagulant therapy, after which he showed gradual recovery. This case highlights a rarely encountered presentation of HIV infection as cerebral venous sinus thrombosis.

Autologous bone marrow-derived stem cells in amyotrophic lateral sclerosis: a pilot study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no effective treatment. Stem cell therapy may be one of the promising treatment options for such patients. AIM: To assess the feasibility, efficacy and safety of autologous bone marrow-derived stem cells in patients of ALS. SETTINGS AND DESIGN: We conducted an open-label pilot study of autologous bone marrow-derived stem cells in patients with ALS attending the Neurology Clinic of a tertiary care referral centre. MATERIALS AND METHODS: Ten patients with ALS with mean revised ALS Functional Rating Scale (ALSFRS-R) score of 30.2 (± 10.58) at baseline received intrathecal autologous bone marrow-derived stem cells. Primary end point was improvement in the ALSFRS-R score at 90, 180, 270 and 365 days post therapy. Secondary endpoints included ALSFRS-R subscores, time to 4-point deterioration, median survival and reported adverse events. Paired t-test was used to compare changes in ALSFRS-R from baseline and Kaplan-Meier analysis was used for survival calculations. RESULTS: There was no significant deterioration in ALSFRS-R composite score from baseline at one-year follow-up (P=0.090). The median survival post procedure was 18.0 months and median time to 4-point deterioration was 16.7 months. No significant adverse events were reported. CONCLUSION: Autologous bone marrow-derived stem cell therapy is safe and feasible in patients of ALS. Short-term follow-up of ALSFRS-R scores suggests a trend towards stabilization of disease. However, the benefit needs to be confirmed in the long-term follow-up period.

Prevalence of Patent Foramen Ovale in North Indian Cryptogenic Young Strokes.

Background: : Strokes of the undetermined cause or cryptogenic strokes (CS) account for 30-40% of ischemic strokes. Paradoxical embolism secondary to patent foramen ovale (PFO) may be associated with CS. Transcranial Doppler (TCD) with bubble contrast is a noninvasive bedside tool for diagnosis of right-to-left shunt (RLS) with high sensitivity and specificity. Data on the prevalence of PFO in CS in India are lacking. We determined the prevalence of RLS likely secondary to PFO in cryptogenic young strokes of the north Indian population using TCD with bubble contrast. Patients and Methods: : In this hospital-based prospective cross-sectional study, TCD with bubble contrast was performed in 57 young (age 15 > 45 years) CS and 50 healthy controls for the detection of RLS. The risk of paradoxical embolism (RoPE) score was calculated from various variables such as age, presence of cortical stroke on neuroimaging, and absence of vascular risk factors. Results: : 57 young CS and 50 healthy controls were recruited. TCD with bubble contrast was positive in 31% cases vs 6% in controls (P = 0.001). All patients with TCD positive for RLS had superficial cortical infarcts (P = 0.03). The median RoPE score of our patients was 9 (range: 7-10). Conclusions: : There is a high prevalence of RLS likely secondary to PFO in cryptogenic young strokes in north India. TCD with bubble contrast is an excellent bedside tool for the detection of RLS.

Exposure to Toxocara Canis is not Associated with New-Onset Epilepsy.

Purpose: The association between exposure to Toxocara canis and epilepsy is at the best contentious. Most of previous studies were retrospective, community-based, and contradictory to one another. As the impact of a positive association on the magnitude of epilepsy will be huge especially in developing countries where toxocariasis is common owing to poor hygienic practices, this study was carried out to determine whether exposure to T. canis predisposes to development of epilepsy. Patients and Methods: This case-controlled observational study was carried out a tertiary healthcare center in North India on 120 patients with newly diagnosed epilepsy who presented within 3 months of diagnosis. A total of 120 age- and sex-matched individuals from the same community were chosen as controls. Epilepsy was defined according to ILAE 1993 definition. Serological testing for T. canis was carried out using commercially available ELISA kits. All the positive samples were subjected to Western blot testing for confirmation. Results: The prevalence of antibodies to T. canis was similar in cases (16/120; 13.3%) and controls (16/120; 13.3%). Among the various risk factors, history of pica was significantly associated with T. canis seropositivity, while lack of hand washing was significantly associated with higher risk of epilepsy. Conclusion: Our study could not find any association between exposure to T. canis and epilepsy.

Vascular endothelial growth factor-A (VEGF-A) and chemokine ligand-2 (CCL2) in amyotrophic lateral sclerosis (ALS) patients.

BACKGROUND: Vascular endothelial growth factor-A (VEGF-A) and chemokne ligand-2 (CCL2) levels have been examined in Amyotrophic Lateral Sclerosis (ALS) patients in Western countries. We measured these values in North Indian ALS patients, since these patients display considerably enhanced survival duration. METHODS: Sporadic ALS patients were included on the basis of El Escorial criteria. VEGF-A and CCL2 levels were analyzed in serum and cerebrospinal fluid (CSF) of 50 ALS patients using enzyme linked immunosorbent assay (ELISA) and compared with normal controls. Their levels were adjusted for possible confounders like cigarette smoking, alcohol and meat consumption. RESULTS: Contrary to previous studies, VEGF-A was found to be elevated significantly in serum and CSF in ALS patient population studied. We also found an increase in CCL2 levels in CSF of these ALS patients. Serum and CSF from definite ALS revealed higher VEGF-A as compared to probable and possible ALS. CCL2 was unaltered between definite, probable and possible ALS. Univariate and multivariate analysis revealed a lack of association of smoking, alcohol and meat consumption with VEGF-A and CCL2 levels. CONCLUSIONS: VEGF-A upregulation may indicate an activation of compensatory responses in ALS which may reflect or in fact account for increased survival of North Indian ALS patients after disease onset. The intrathecal synthesis of CCL2 suggests the involvement of adult neural stem cells and microglial activation in ALS pathogenesis which needs further investigation.

Vascular endothelial growth factor-A and chemokine ligand (CCL2) genes are upregulated in peripheral blood mononuclear cells in Indian amyotrophic lateral sclerosis patients.

BACKGROUND: We have earlier shown that protein levels of vascular endothelial growth factor-A (VEGF-A) and chemokine ligand-2 (CCL2) were elevated in Indian amyotrophic lateral sclerosis (ALS) patients. Here, we report the mRNA levels of VEGF-A and CCL2 in Indian ALS patients since they display extended survival after disease onset. METHODS: VEGF-A and CCL2 mRNA levels were measured in peripheral blood mononuclear cells (PBMCs) of 50 sporadic Indian ALS patients using Real Time Polymerase Chain Reaction (PCR) and compared with normal controls (n = 50). Their levels were adjusted for possible confounders like cigarette smoking, alcohol and meat consumption. RESULTS: VEGF-A and CCL2 mRNA levels were found to be significantly elevated in PBMCs in ALS patients as compared to controls. PBMCs from definite ALS revealed higher VEGF-A mRNA expression as compared to probable and possible ALS. CCL2 mRNA levels were found to be unaltered when definite, probable and possible ALS were compared. PBMCs from patients with respiratory dysfunction showed much higher VEGF-A and CCL2 elevation when compared to patients without respiratory dysfunction. No association of smoking, alcohol and meat consumption with VEGF-A and CCL2 was observed after analyzing the data with univariate and multivariate analysis. CONCLUSION: VEGF-A and CCL2 mRNA upregulation in PBMCs may have a clinico-pathological/etiological/epidemiological association with ALS pathogenesis. The cross-cultural and cross-ethnic investigations of these molecules could determine if they have any role in enhancing the mean survival time unique to Indian ALS patients.

Short-course of prednisolone in solitary cysticercus granuloma: a randomized, double-blind, placebo-controlled trial.

PURPOSE: To determine the effect of administration of a short course of prednisolone on seizure and radiologic outcome in patients with solitary cysticercus granuloma (SCG). METHODS: One hundred forty-eight subjects presenting with new-onset seizures (<15 days duration) and with SCG demonstrated on imaging studies were randomly allocated to either treatment with prednisolone (40-60 mg/day for 2 weeks) or placebo in addition to standard antiepileptic drug therapy. The subjects were followed up for seizure recurrence for 9 months. Repeat computed tomography (CT, at 3 months) and magnetic resonance imaging (MRI, at 6 months) to evaluate resolution and calcification of the lesion. KEY FINDINGS: There was no difference in the proportion of subjects with seizure recurrence during the follow-up period in the treatment (n = 16, 21.9%) and control (n = 19, 25.33%) groups (p = 0.7). However, generalized seizures occurred in a significantly lesser proportion of subjects in the treatment group (n = 3, 15.79%) in comparison to the control group (n = 12, 60.00%) (p = 0.015). There were no significant differences in the proportion of subjects with complete resolution of the SCG on repeat CT at 3 months [treatment group (27, 46.7%) and control group (23, 39.8%); p = 0.453] and repeat MRI at 6 months [treatment group (28, 46.7%) and control group (21, 38.9%); p = 0.402]. SIGNIFICANCE: The administration of a short course of prednisolone does not offer significant improvement in seizure control, although a benefit in terms of reducing the likelihood of generalized seizures is possible. Furthermore, it does not improve the chances of resolution of the SCG on follow-up imaging studies.

Marburg's disease: a diagnostic dilemma.

This report describes the clinical, radiological and autopsy findings of a young male suffering from acute, monophasic demyelinating disease presenting with acute onset of altered sensorium and a short past history of progressive multiple neurological deficits. The radiological findings revealed acute infarcts in the territory of anterior cerebral artery. The antemortem diagnosis centred on an infective (tubercular) aetiology leading to demyelination based on presence of tubercle bacilli in bronchoalveolar lavage (BAL) fluid. The autopsy revealed multiple subacute and acute plaques showing demyelination, giant astrocytes, numerous macrophages and little perivascular inflammation, thereby confirming the diagnosis of Marburg's type of multiple sclerosis. Marburg's type is a fulminant demyelinating disorder characterised by a severe, rapidly evolving clinical course. Death occurs due to brain stem involvement or severe widespread cerebral lesions.

Bacopa monniera Attenuates Scopolamine-Induced Impairment of Spatial Memory in Mice.

Scopolamine, an anticholinergic, is an attractive amnesic agent for discerning the action of candidate antiamnesic drugs. Bacopa monniera Linn (Syn. Brahmi) is one such antiamnesic agent that is frequently used in the ancient Indian medical system. We have earlier reported the reversal of diazepam-induced amnesia with B. monniera. In this study we wanted to test if scopolamine-induced impairment of spatial memory can also be ameliorated by B. monniera using water maze mouse model. The objective of study was to study the effect of B. monniera on scopolamine-induced amnesia. We employed Morris water maze scale to test the amnesic effect of scopolamine and its reversal by B. monniera. Rotarod test was conducted to screen muscle coordination activity of mice. Scopolamine significantly impaired the acquisition and retrieval of memory producing both anterograde and retrograde amnesia. Bacopa monniera extract was able to reverse both anterograde and retrograde amnesia. We propose that B. monniera's effects on cholinergic system may be helpful for developing alternative therapeutic approaches for the treatment of Alzheimer's disease.