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Lewy body dementia (LBD) is the second most prevalent neurodegenerative dementia and it causes more morbidity and mortality than Alzheimer’s disease. Several genetic associations of LBD have been reported and their functional implications remain uncertain. Hence, we aimed to do a systematic review of all gene expression studies that investigated people with LBD for improving our understanding of LBD molecular pathology and for facilitating discovery of novel biomarkers and therapeutic targets for LBD.
We systematically reviewed five online databases (PROSPERO protocol: CRD42017080647) and assessed the functional implications of all reported differentially expressed genes (DEGs) using Ingenuity Pathway Analyses.
We screened 3,809 articles and identified 31 eligible studies. In that, 1,242 statistically significant (p < 0.05) DEGs including 70 microRNAs have been reported in people with LBD. Expression levels of alternatively spliced transcripts of SNCA, SNCB, PRKN, APP, RELA, and ATXN2 significantly differ in LBD. Several mitochondrial genes and genes involved in ubiquitin proteasome system and autophagy–lysosomal pathway were significantly downregulated in LBD. Evidence supporting chronic neuroinflammation in LBD was inconsistent. Our functional analyses highlighted the importance of ribonucleic acid (RNA)-mediated gene silencing, neuregulin signalling, and neurotrophic factors in the molecular pathology of LBD.
α-synuclein aggregation, mitochondrial dysfunction, defects in molecular networks clearing misfolded proteins, and RNA-mediated gene silencing contribute to neurodegeneration in LBD. Larger longitudinal transcriptomic studies investigating biological fluids of people living with LBD are needed for molecular subtyping and staging of LBD. Diagnostic biomarker potential and therapeutic promise of identified DEGs warrant further research.
Cognitive impairment and depression are among the most prevalent and most disabling non-motor symptoms in Parkinson’s disease (PD). The genetic factors that are associated with these symptoms remain uncertain. This systematic review aims to summarise the prevailing evidence from all genetic association studies investigating the genetic variants associated with cognitive impairment and depressive symptoms in people with PD.
A systematic review using five online databases: PubMed, PsycINFO, CINAHL, EMBASE and OpenGrey (PROSPERO protocol: CRD42017067431). We completed the quality assessment using the Q-Genie tool.
2353 articles were screened, and 43 articles were found to be eligible to be included. A meta-analysis of studies investigating LRRK2 rs34637584 confirmed that the minor allele carriers had significantly less cognitive impairment (p = 0.015). Further meta-analyses showed that GBA variants rs76763715 (p < 0.001) and rs421016 (p = 0.001) were significantly associated with more cognitive impairment in people with PD. Minor alleles of GBA variants rs76763715, rs421016, rs387906315 and rs80356773 were associated with more depressive symptoms in PD. Moreover, APOE ε4 allele has been associated with more cognitive impairment in PD. BDNF (rs6265) and CRY1 (rs2287161) variants have been associated with more depressive symptoms in people with PD.
PD carriers of GBA variants are at high risk for cognitive decline and depression. Screening for these variants may facilitate early identification and effective management of these non-motor symptoms. The molecular mechanisms underlying favourable cognitive functioning in LRRK2 rs34637584 variant carriers warrant further investigation.
Pharmacological interventions for Lewy body dementia (LBD), especially for its non-cognitive symptoms, are limited in their efficacy and tolerability. Clinicians are often uncertain about non-pharmacological interventions and their efficacy in managing cognitive and non-cognitive symptoms of LBD. Therefore, we aimed to systematically review the existing literature on non-pharmacological interventions for people with LBD.
We carried out a systematic search using six databases. All human studies examining impact of any non-pharmacological intervention on LBD were assessed for cognitive, physical, psychiatric, and quality-of-life outcomes. Study quality was assessed by Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies and the CARE criteria checklist.
Prevailing evidence supporting the efficacy of non-pharmacological interventions is weak. We screened 1,647 papers. Fifteen studies (n = 61) including 11 case reports were found eligible for this systematic review. Interventions and reported outcomes were heterogeneous. Deep brain stimulation of the nucleus basalis of Meynert reportedly conferred cognitive benefit. Electroconvulsive therapy and repetitive transcranial magnetic stimulation have been reported to ameliorate depressive symptoms. Transcranial direct current stimulation was observed to improve attention. Exercise-based interventions reportedly improve various clinically important outcomes. Spaced retrieval memory training and environmental intervention for “mirror sign” have also been reported.
Several non-pharmacological interventions have been studied in LBD. Although evidence supporting their efficacy is not robust, prevailing preliminary evidence and limitations of available pharmacological interventions indicate the need to consider appropriate non-pharmacological interventions, while planning comprehensive care of LBD patients. Larger trials evaluating the efficacy of non-pharmacological interventions for LBD are needed.
Despite clozapine's superior clinical efficacy in treatment-resistant schizophrenia (TRS), its adverse effects, need for periodic leukocyte monitoring, cost and variable clinical outcomes mandate a clinical need to predict its treatment response. Although cytochrome P450 1A2 (CYP1A2) is the principal determinant of metabolism of clozapine, the role of CYP1A2 gene in the clinical response to clozapine is uncertain. Hence, we investigated its association with treatment responses and adverse events of clozapine in TRS.
We evaluated four single nucleotide polymorphisms (SNP) in the CYP1A2 gene, clinical responses and serum clozapine levels in 101 consecutive patients with TRS on stable doses of clozapine. We defined clozapine response a priori and investigated allelic and genotypic associations. We assessed the socio-demographic and clinical profiles, premorbid adjustment, traumatic life events, cognition and disability of the participants, using standard assessment schedules for appropriate multivariate analyses.
Our results revealed that CYP1A2 gene SNP (*1C, *1D, *1E and *1F) were not associated with clozapine treatment response, adverse effects, serum clozapine levels or with disability (p values > 0.10).
As CYP1A2 gene SNP do not help to predict the clinical response to clozapine, routine screening for them prior to start clozapine is currently unwarranted. We suggest future longitudinal genome-wide association studies investigating clinical and pharmacogenetic variables together.
Objective: The ability to reflect rationally on one's own anomalous experiences and to recognise that their conclusions are incorrect is called as cognitive insight. It influences the delusion proneness of patients with schizophrenia. Structured instruments to assess cognitive insight have not been validated in any Indian languages so far. Hence, we aimed to evaluate the validity and factor structure of Tamil version of Beck Cognitive Insight Scale (BCIS-T).
Methods: One hundred and fifty consecutive patients with schizophrenia completed BCIS-T. We assessed their clinical insight with the reference standard, Schedule for Assessment of Insight-Expanded version (SAI-E). An independent psychiatrist evaluated their psychopathology using Brief Psychiatric Rating Scale (BPRS).
Results: BCIS-T was internally consistent with Cronbach's α 0.67 and Guttman's split-half coefficient as 0.63. BCIS-T composite index documented convergent validity with SAI-E total score (ρ = 0.38; p < 0.001) and discriminant validity with BPRS (ρ = −0.02; p = 0.85). Factor analysis showed a four-factor structure, namely self-certainty, self-reflectiveness, openness to external feedback and infallibility of self-reflection. BCIS-T composite index had significant linear relationship with clinical insight and treatment compliance on multivariate analyses (p < 0.01).
Conclusion: Our findings support the validity of BCIS-T to assess cognitive insight of the patients with schizophrenia. We suggest addressing the intricacies of cognitive insight beyond the traditional two-dimensional models in cross-cultural settings.
UBVRI photometry and medium resolution spectroscopy of two Type Ia supernovae, SN 2009an and SN 2009ig, are presented. Their Δm15(B) indicate these two SNe marginally deviate from “normal” Type Ia events. Spectroscopically, both SNe belong to the low velocity gradient group. The estimated mass of 56Ni ejected is almost a factor of two different for these two objects, with the estimates being ~0.4M⊙ for SN 2009an and ~0.8 M⊙ for SN 2009ig.
Emergency situations such as biological or chemical incidents require prompt decision making. The problem is that the authorized personnel responsible for conduction the response operations might lack the knowledge about the agent's biological, chemical and epidemiological characteristics that would influence the impact of the incident. Thus the effect of response operations on lives and assets could hardly be anticipated. The paper suggests simulation based approach to provide appropriate decision making support in such situations. The simulation would imitate the development of an emergency situation under various scenarios and help to determine the proper response operations by which the casualties and loss of assets would be minimized. The aim of the paper is to present the simulation of a spread of an agent in an environment and the corresponding impact on population. The simulation is based on a model with incorporated knowledge about environmental and agent characteristics such as weather conditions, transmission, fatality, incubation period combined also with demographic information. The provided simulation forms a part of the proposed non-military decision support framework for emergency response operations during biochemical incidents.