Ram J. Bishnoi

Serum Interleukin (IL)-15 as a biomarker of Alzheimer's disease

Interleukin (IL-15), a pro-inflammatory cytokine has been studied as a possible marker of Alzheimer’s disease (AD); however its exact role in neuro-inflammation or the pathogenesis AD is not well understood yet. A Multiple Indicators Multiple Causes (MIMIC) approach was used to examine the relationship between serum IL-15 levels and AD in a well characterized AD cohort, the Texas Alzheimers Research and Care Consortium (TARCC). Instead of categorical diagnoses, we used two latent construct d (for dementia) and g’ (for cognitive impairments not contributing to functional impairments) in our analysis. The results showed that the serum IL-15 level has significant effects on cognition, exclusively mediated by latent construct d and g’. Contrasting directions of association lead us to speculate that IL-15’s effects in AD are mediated through functional networks as d scores have been previously found to be specifically related to default mode network (DMN). Our finding warrants the need for further research to determine the changes in structural and functional networks corresponding to serum based biomarkers levels.

Utility of repetitive transcranial stimulation as an augmenting treatment method in treatment-resistant depression.

About 30 to 46% of patients with major depressive disorder (MDD) fail to fully respond to initial antidepressants. Treatment-resistant depression (TRD) is a severely disabling disorder with no proven treatment options; novel treatment methods like rTMS can be used as augmentation to ongoing pharmacotherapy or as a solitary method of treatment. To evaluate the utility of repetitive transcranial magnetic stimulation as an augmenting method in TRD. In an open-label study, 21 patients with DSM-IV MDD without psychotic features who had failed to respond to an adequate trial of at least 2 antidepressants were given rTMS therapy for 4 weeks, keeping the dose of pre-existing antidepressants unchanged. High-frequency (10 Hz) stimulations were delivered over left dorsolateral prefrontal cortex at intensity of 110% of patients motor threshold. Treatment response was defined as a reduction in score on the Hamilton Rating Scale for Depression (HAM-D) from baseline to end of treatment. Secondary efficacy measures included scores on the Clinical Global Impressions-Change and -Severity scales. At the end of 4 weeks, 19 patients completed the 4-week study and were assessed. In ITT analysis, the mean HAM-D17 scores were reduced from 30.80±5.00 to 19.00±6.37 (t=8.27, P<0.001). Only four patients reported headache, but there was no discontinuation due to adverse effects. The study indicates the potential utility of rTMS as an augmenting agent in TRD. Adequately powered, randomized controlled trials are necessary to evaluate the role of rTMS in TRD.

Vitamin D Binding Protein as a Serum Biomarker of Alzheimer's Disease

Vitamin D binding protein (VDBP), a multifunctional protein, has been found to be elevated in the cerebrospinal fluid (CSF) of neurodegenerative disorder cases, implicating it in the pathogenesis of Alzheimers disease (AD). However, the contribution of VDBP to AD has not been fully explored. We used a Multiple Indicators Multiple Causes (MIMIC) approach to examine the relationship between serum VDBP levels and cognitive performance in a well characterized AD cohort, the Texas Alzheimers Research and Care Consortium (TARCC). Instead of categorical diagnoses, we used a latent dementia phenotype (d), which has been validated in several prior studies using this dataset. We found that serum VDBP levels are significantly positively associated with d scores, which in turn are inversely related to cognitive performance. This suggests that d mediates the adverse effects of serum VDB on cognition and therefore that its effects are specifically dementing. d scores are also specifically related to default mode network (DMN) structure. VDBP acts as an amyloid-β (Aβ) scavenger, and Aβ deposition in the DMN is seen in the pre-clinical stages of AD. We speculate then that serum effects of VDBP are mediated through changes in DMN structure or function, most probably via Aβ. Aβ affects the DMN early in the course of AD. Therefore, raised serum VDBP levels may be a useful indicator of future dementia and/or dementia conversion. This might be confirmed through longitudinal analysis of TARCC data.

Comprehensibility of translated informed consent documents used in clinical research in psychiatry

Background: Informed consent forms are required in all clinical trials which are approved by an independent Ethics Committee before practical use in the trials. However, how much the average subject actually understands of the information contained in these informed consent forms is uncertain. Aim: In a cross sectional study, the translated informed consent forms used in psychiatric clinical trials were assessed with respect to their ease of readability. Materials and Methods: We analyzed 30 informed consent forms translated from English to Hindi used in multinational and multicentre psychiatric clinical trials sponsored by different sponsors. We examined consent forms for readability scores and factors that might relate to readability. Results: The mean readability score for the informed consent forms, determined by the Flesch-Kincaid Grade Level Index (FKGL) was grade levels of 13.66. The ease of readability assessed by the Flesch Reading Ease Score (FRES) was 46.08 suggesting significant complexity of the texts. These values carry even more significance when the average years of schooling for India as a whole are 6.2 years. Conclusion: Our results show that the most informed consent forms were too complex to understand by an average adult subject. We suggest reducing this complexity and increasing the ease of readability so those average subjects receive the intended information as exactly as it could be. This can be achieved by few simple measures like improving the deficiencies in translation processes, encouraging the investigators to participate while preparing these forms, and enhanced understanding of the site specific requirements, namely culture, language (dialect), general literacy rate, etc.

Utility of repetitive transcranial magnetic stimulation as an augmenting treatment method in treatment-resistant depression.

Background: About 30–46% of patients with major depressive disorder (MDD) fail to fully respond to initial antidepressants. Treatment-resistant depression is a severely disabling disorder with no proven treatment options; novel treatment methods, such as repetitive transcranial magnetic stimulation (rTMS) can be used as augmentation to ongoing pharmacotherapy or as a solitary method of treatment. Aim: To evaluate the utility of rTMS as an augmenting method in treatment-resistant depression. Materials and Methods: In an open-label study, 21 patients with DSM-IV MDD without psychotic features who had failed to respond to an adequate trial of at least 2 antidepressants were given rTMS therapy for 4 weeks keeping the dose of pre-existing antidepressants unchanged. High-frequency (10 Hz) stimulations were delivered over left dorsolateral prefrontal cortex at an intensity of 110% of the patients motor threshold. Treatment response was defined as a reduction in score on the Hamilton Rating Scale for Depression (HAM-D) from baseline to end of treatment. Secondary efficacy measures included scores on the Clinical Global Impressions-Change and -Severity scales. Results: At the end of 4 weeks, 19 patients completed the 4 weeks study and were assessed. In ITT analysis the mean HAM-D17 scores were reduced from 30.80±5.00 to 19.00±6.37 (t=8.27, P<0.001). Only 4 patients reported headache but there was no discontinuation due to adverse effects. Conclusions: The study indicates the potential utility of rTMS as an augmenting agent in treatment-resistant depression. Adequately powered, randomized controlled trials are necessary to evaluate the role of rTMS in treatment-resistant depression.

Serum proteins mediate depression’s association with dementia

The latent variable “δ” (for “dementia”) uniquely explains dementia severity. Depressive symptoms are independent predictors of δ. We explored 115 serum proteins as potential causal mediators of the effect of depressive symptoms on δ in a large, ethnically diverse, longitudinal cohort. All models were adjusted for age, apolipoprotein E, education, ethnicity, gender, hemoglobin A1c, and homocysteine, and replicated in randomly selected 50% subsets. Alpha1-antitrypsin (A1AT), FAS, Heparin-binding EGF-like Growth Factor (HB-EGF), Insulin-like Growth Factor-1 (IGF-1), Luteinizing Hormone (LH), Macrophage Inflammatory Protein type 1 alpha (MIP-1α), Resitin, S100b, Tissue Inhibitor of Metalloproteinase type 1 (TIMP-1), and Vascular Cell Adhesion Molecule type 1 (VCAM-1) each were partial mediators of depression’s association with δ. These proteins may offer targets for the treatment of depression’s specific effect on dementia severity and Alzheimer’s Disease (AD) conversion risk.

Few serum proteins mediate APOE’s association with dementia

The latent variable “δ” (for “dementia”) appears to be uniquely responsible for the dementing aspects of cognitive impairment. Age, depression, gender and the apolipoprotein E (APOE) e4 allele are independently associated with δ. In this analysis, we explore serum proteins as potential mediators of APOE’s specific association with δ in a large, ethnically diverse longitudinal cohort, the Texas Alzheimer’s Research and Care Consortium (TARCC). APOE was associated only with C-Reactive Protein (CRP), Adiponectin (APN) and Amphiregulin (AREG), although the latter two’s associations did not survive Bonferroni correction for multiple comparisons. All three proteins were associated with δ and had weak potential mediation effects on APOE’s association with that construct. Our findings suggest that APOE’s association with cognitive performance is specific to δ and partially mediated by serum inflammatory proteins. The majority of APOE’s significant unadjusted effect on δ is unexplained. It may instead arise from direct central nervous system effects, possibly on native intelligence. If so, then APOE may exert a life-long influence over δ and therefore all-cause dementia risk.

Methodological issues associated with preclinical drug development and increased placebo effects in schizophrenia clinical trials.

ABSTRACT Recent failures to detect efficacy in clinical trials investigating pharmacological treatments for schizophrenia raise concerns regarding the potential contribution of methodological shortcomings to this research. This review provides an examination of two key methodological issues currently suspected of playing a role in hampering schizophrenia drug development; 1) limitations on the translational utility of preclinical development models, and 2) methodological challenges posed by increased placebo effects. Recommendations for strategies to address these methodological issues are addressed.

Serum protein mediators of dementia and aging proper

The latent variable “δ” (for “dementia”) appears to be uniquely responsible for the dementing aspects of cognitive impairment. Age, depressive symptoms, gender and the apolipoprotein E (APOE) ε4 allele are independently associated with δ. In this analysis, we explore serum proteins as potential mediators of ages specific association with δ in a large, ethnically diverse longitudinal cohort, the Texas Alzheimers Research and Care Consortium (TARCC). 22 serum proteins were recognized as partial mediators of ages association with δ. These include Insulin-like Growth Factor-Binding Protein 2 (IGF-BP2), which we had previously associated with age-specific cognitive change, and both Pancreatic Polypeptide (PP) and von Willebrand Factor (vWF), previously associated with δ. Nine other δ-related proteins were not confirmed by this ethnicity adjusted analysis. Our findings suggest that ages association with the disabling fraction of cognitive performance is partially mediated by serum proteins, somatomedins and hormones. Those proteins may offer targets for the specific treatment of age-related effects on dementia severity and conversion risk.

Clinical potential of allopurinol in the treatment of bipolar disorder

It is with great interest that I read the letter to the editor titled “should publications be the only means for assessment?”[1] The letter seemed to voice the general sentiments among the members of the multitasking clinician-academician researcher community like us. Infact, the title of the letter would be the main culprit behind a number of issues plaguing the research world like the rise in plagiarism, unethical research reporting practices, authorship controversies and burn out of researchers. Infact, the issue of burn out in researchers has been aptly termed “publish and perish” in place of the usual adage of “publish or perish” by an author.[2] The solution lies in a comprehensive assessment in terms of assessment of teaching abilities (teaching awards, peer evaluation, learner evaluation etc.); clinical skills and patient care abilities (objective patient feedback, prescription auditing, peer evaluation etc.) mentoring ability (student feedback) assessment of administrative abilities (involvement in institutional committees, organizing workshops etc.) personal qualities (ethical standards, leadership quality, community work etc.) and research acumen (publications and projects).[3] Assessment in all these domains, though cumbersome, is essential for accurate judgment for recruitment or promotion purposes. Efforts should be taken by regulatory or guiding authorities to objectify such a multipronged rating system that should eventually replace the undue emphasis of the number of publications. It would also be a partial solution to many of the controversies surrounding bio-medical research today.