46 research outputs found
Cognitive leisure activities and future risk of cognitive impairment and dementia: systematic review and meta-analysis
BACKGROUND: As life expectancies continue to rise, modifiable lifestyle factors that may prevent cognitive decline and dementia in later life become increasingly important in order to maintain quality of life in old age. METHODS: Five meta-analyses were conducted on data from papers identified in a systematic review. Studies were grouped according to outcomes (dementia, cognitive impairment including amnestic Mild Cognitive Impairment (aMCI), Mild Cognitive Impairment (MCI), and cognitive decline) and output (risk (RR), odds (OR), or hazard ratios (HR)). RESULTS: Nineteen studies met our inclusion criteria and quality assessments. Four of five meta-analyses showed significant associations between participation in cognitive leisure activities and reduced risk of cognitive impairment (OR = 0.69, 95% CI: 0.56-0.85) and dementia (HR = 0.58, 95% CI: 0.46-0.74; RR = 0.61, 95% CI: 0.42-0.90; OR = 0.78, 95% CI: 0.67-0.90). However, one pooled analysis of cognitive impairment studies did not reach significance (HR = 0.85, 95% CI: 0.71-1.02). Mentally stimulating leisure activities were significantly associated with later life cognition (ÎČ = 0.11, p = 0.05), better memory (ÎČ = 0.20, 95% CI: 0.11-0.29), speed of processing (ÎČ = 0.37, 95% CI: 0.29-0.45), and executive functioning (ÎČ = 0.23, 95% CI: 0.15-0.29), and less decline in overall cognition (ÎČ = -0.23, p < 0.01), language (ÎČ = -0.11, p < 0.05), and executive functioning (ÎČ = -0.13, p < 0.05). Activities were also shown to reduce rate of cognitive decline (estimate = 0.03, SE = 0.01, p = 0.00). CONCLUSIONS: There is increasing evidence that participation in cognitively stimulating leisure activities may contribute to a reduction of risk of dementia and cognitive impairment in later life. Promoting involvement in such activities across lifespan could be an important focus for primary prevention strategies for governments and health services
Functional characterisation of the amyotrophic lateral sclerosis risk locus GPX3/TNIP1
Background
Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this.
Methods
The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (Ncases = 20,806, Ncontrols = 59,804) with âomics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray Ntotal = 942, protein Ntotal = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO).
Results
SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 Ă 10â6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 Ă 10â3, adjusted R2 = 0.042, Beffect = 27.4 ± 13.3âng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28âmm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53âmm/s, respectively, p for all <â0.0001), which were rescued with gpx3 expression, with no phenotype identified with tnip1 KD or gpx3 overexpression.
Conclusions
These results support GPX3 as a lead ALS risk gene in this locus, with more data needed to confirm/reject a role for TNIP1. This has implications for understanding disease mechanisms (GPX3 acts in the same pathway as SOD1, a well-established ALS-associated gene) and identifying new therapeutic approaches. Few previous examples of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings
Functional characterisation of the amyotrophic lateral sclerosis risk locus GPX3/TNIP1
Background: Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this. // Methods: The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (Ncases = 20,806, Ncontrols = 59,804) with âomics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray Ntotal = 942, protein Ntotal = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO). // Results: SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 Ă 10â6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 Ă 10â3, adjusted R2 = 0.042, Beffect = 27.4 ± 13.3âng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28âmm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53âmm/s, respectively, p for all <â0.0001), which were rescued with gpx3 expression, with no phenotype identified with tnip1 KD or gpx3 overexpression. // Conclusions: These results support GPX3 as a lead ALS risk gene in this locus, with more data needed to confirm/reject a role for TNIP1. This has implications for understanding disease mechanisms (GPX3 acts in the same pathway as SOD1, a well-established ALS-associated gene) and identifying new therapeutic approaches. Few previous examples of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings
Improvement of attention span and reaction time with hyperbaric oxygen treatment in patients with toxic injury due to mold exposure
It is, by now, well established that mold toxins (mycotoxins) can cause significant adverse health effects. In this study, 15 subjects who developed an attention deficit disorder (ADD) and slowing of reaction time at the time of exposure to mold toxins were identified. Deficits in attention span and reaction time were documented not only by taking a careful history, but also by performing a Test of Variables of Attention (TOVA). The TOVA test provides an objective measure of these two variables. It was found that mold-exposed subjects show statistically significant decreases in attention span and significant increases in reaction time to stimuli compared to controls. After ten sessions of hyperbaric oxygen treatment (HBOT), a statistically significant improvement was seen in both measures. This preliminary study suggests promising outcomes in treating mold-exposed patients with hyperbaric oxygen
Effect of the severity of liver dysfunction on the minimum alveolar concentration of sevoflurane responding to an electronic stimulation in cirrhotic patients
The pKa of the general acid/base carboxyl group of a glycosidase cycles during catalysis: A 13 C-NMR study of Bacillus circulans xylanase: Biochemistry
NRC publication: Ye