Dementia risk reduction: why haven't the pharmacological risk reduction trials worked? An in-depth exploration of seven established risk factors.
Ontology highlight
ABSTRACT:
SUBMITTER: Peters R
PROVIDER: S-EPMC8655351 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Evidence from controlled trials encourages the intake of dietary pulses (beans, chickpeas, lentils and peas) as a method of improving dyslipidemia, but heart health guidelines have stopped short of ascribing specific benefits to this type of intervention or have graded the beneficial evidence as low. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effect of dietary pulse intake on established therapeutic lipid targets for cardiovascular risk reduction.We searched electronic databases and bibliographies of selected trials for relevant articles published through Feb. 5, 2014. We included RCTs of at least 3 weeks' duration that compared a diet emphasizing dietary pulse intake with an isocaloric diet that did not include dietary pulses. The lipid targets investigated were low-density lipoprotein (LDL) cholesterol, apolipoprotein B and non-high-density lipoprotein (non-HDL) cholesterol. We pooled data using a random-effects model.We identified 26 RCTs (n = 1037) that satisfied the inclusion criteria. Diets emphasizing dietary pulse intake at a median dose of 130 g/d (about 1 serving daily) significantly lowered LDL cholesterol levels compared with the control diets (mean difference -0.17 mmol/L, 95% confidence interval -0.25 to -0.09 mmol/L). Treatment effects on apolipoprotein B and non-HDL cholesterol were not observed.Our findings suggest that dietary pulse intake significantly reduces LDL cholesterol levels. Trials of longer duration and higher quality are needed to verify these results.ClinicalTrials.gov, no. NCT01594567.
| S-EPMC4016088 | biostudies-literature
Project description:The FK506-binding protein 51 (FKBP51) is an Hsp90-associated co-chaperone which regulates steroid receptors and kinases. In pancreatic cancer cell lines, FKBP51 was shown to recruit the phosphatase PHLPP to facilitate dephosphorylation of the kinase Akt, which was associated with reduced chemoresistance. Here we show that in addition to FKBP51 several other members of the FKBP family bind directly to Akt. FKBP51 can also form complexes with other AGC kinases and mapping studies revealed that FKBP51 interacts with Akt via multiple domains independent of their activation or phosphorylation status. The FKBP51-Akt1 interaction was not affected by FK506 analogs or Akt active site inhibitors, but was abolished by the allosteric Akt inhibitor VIII. None of the FKBP51 inhibitors affected AktS473 phosphorylation or downstream targets of Akt. In summary, we show that FKBP51 binds to Akt directly as well as via Hsp90. The FKBP51-Akt interaction is sensitive to the conformation of Akt1, but does not depend on the FK506-binding pocket of FKBP51. Therefore, FKBP inhibitors are unlikely to inhibit the Akt-FKBP-PHLPP network.
| S-EPMC3585324 | biostudies-literature
Project description:A 2013 systematic review and Delphi consensus study identified 12 modifiable risk and protective factors for dementia, which were subsequently merged into the "LIfestyle for BRAin health" (LIBRA) score. We systematically evaluated whether LIBRA requires revision based on new evidence. To identify modifiable risk and protective factors suitable for dementia risk reduction, we combined an umbrella review of systematic reviews and meta-analyses with a two-round Delphi consensus study. The review of 608 unique primary studies and opinions of 18 experts prioritized six modifiable factors: hearing impairment, social contact, sleep, life course inequalities, atrial fibrillation, and psychological stress. Based on expert ranking, hearing impairment, social contact, and sleep were considered the most suitable candidates for inclusion in updated dementia risk scores. As such, the current study shows that dementia risk scores need systematic updates based on emerging evidence. Future studies will validate the updated LIBRA score in different cohorts. HIGHLIGHTS: An umbrella review was combined with opinions of 18 dementia experts. Various candidate targets for dementia risk reduction were identified. Experts prioritized hearing impairment, social contact, and sleep. Re-assessment of dementia risk scores is encouraged. Future work should evaluate the predictive validity of updated risk scores.
| S-EPMC10984497 | biostudies-literature
Project description:The mechanism underlying the effects of anti-vascular endothelial growth factor (VEGF) antibody in retinal vein occlusion (RVO) treatment is poorly understood, partly due to the lack of RVO animal models that mimic clinical pathology. The aims of this study were to establish a suitable RVO model, clarify the pathogenic mechanisms, and evaluate the effects of anti-VEGF antibody in the model. Mouse retinal veins were occluded by laser photocoagulation after rose bengal injection. Reduction of the b/a wave amplitude ratio, retinal nonperfusion, cystoid edema, and hard exudates were observed after occlusion, and expression of RVO-related genes was altered. Administration of anti-VEGF antibody immediately, or 7 days, after occlusion resulted in reduction and increase of the nonperfused area, respectively. We conclude that the present model will be useful for clarification of the pathogenic mechanisms, and that the timing of anti-VEGF antibody administration is important for the successful amelioration of retinal nonperfusion.
| S-EPMC5333144 | biostudies-literature
Project description:BackgroundIndividuals with a parental family history of dementia have an increased risk of developing dementia because they share their genes as well as their psychosocial behaviour. Due to this increased risk and their experience with dementia, they may be particularly eager to receive information regarding dementia risk reduction (DRR). This study evaluated the knowledge, beliefs and attitudes towards dementia and DRR among descendants of people with dementia.MethodUsing a semi-structured topic guide, three focus group discussions were conducted consisting of 12 female (80%) and 3 male (20%) descendants of people with dementia with a mean (± SD) age of 48.8 (± 12) years. Focus group discussions were audio recorded and transcribed. Each transcript was analysed thoroughly, and where appropriate, a code was generated and assigned by two researchers independently. Then, similar codes were grouped together and categorized into themes.ResultsThe items in the topic guide could only be addressed after participants had been given the opportunity to share their experiences of having a parent with dementia. Participants were unaware or uncertain about the possibility of reducing the risk of developing dementia and therefore hesitant to assess their dementia risk without treatment options in sight. Moreover, participants indicated that their general practitioner only gave some information on heritability, not on DRR. Although participants identified a large number of modifiable risk factors as a group during the group discussions, they were eager to receive more information on dementia and DRR. In the end, participants adopted a more positive attitude towards a DRR programme and provided suggestions for the development of future DRR programmes.ConclusionsAlthough the research aim was to evaluate the knowledge, beliefs and attitudes towards dementia and DRR, sharing experiences of having a parent with dementia seemed a prerequisite for considering participants' own risk of developing dementia and participating in a DRR programme. Knowledge of dementia and DRR was limited. Due to unawareness of the possibility of reducing dementia risk, participants were hesitant about assessing their dementia risk. Group discussions positively changed the perception of dementia risk assessment and participants' willingness to participate in a DRR programme.
| S-EPMC8265097 | biostudies-literature
Project description:Abdominal aortic aneurysm (AAA) is characterized by transmural infiltration of myeloid cells at the vascular injury site. Previously, we reported preventive effects of Notch deficiency on the development of AAA by reduction of infiltrating myeloid cells. In this study, we examined if Notch inhibition attenuates the progression of pre-established AAA and potential implications. Pharmacological Notch inhibitor (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester; DAPT) was administered subcutaneously three times a week starting at day 28 of angiotensin II (AngII) infusion. Progressive increase in pulse wave velocity (PWV), maximal intra-luminal diameter (MILD) and maximal external aortic diameter (MEAD) were observed at day 56 of the AngII. DAPT prevented such increase in MILD, PWV and MEAD (P < 0.01). Histologically, the aortae of DAPT-treated Apoe-/- mice had significant reduction in inflammatory response and elastin fragmentation. Naked collagen microfibrils and weaker banded structure observed in the aortae of Apoe-/- mice in response to AngII, were substantially diminished by DAPT. A significant decrease in the proteolytic activity in the aneurysmal tissues and vascular smooth muscle cells (vSMCs) was observed with DAPT (P < 0.01). In human and mouse AAA tissues, increased immunoreactivity of activated Notch signaling correlated strongly with CD38 expression (R2 = 0.61). Collectively, we propose inhibition of Notch signaling as a potential therapeutic target for AAA progression.
| S-EPMC6748927 | biostudies-literature
Project description:ObjectiveNon-pharmacological therapies (NPTs) have received increasing attention from researchers as a category of treatment to improve cognitive impairment in patients with dementia because of their fewer side effects. In this study, photobiomodulation (PBM), enriched environment (EE), exercise therapy (ET), computerized cognitive training (CCT), and cognitive stimulation therapy (CST) were selected to compare the effects of NPTs that improve dementia by quantifying information from randomized controlled trials (RCTs).MethodsWe did a systematic review and network meta-analysis. We searched PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), China National Knowledge Infrastructure Database, Wan Fang Database, Chinese Biomedical Literature Database, Web of Science, and VIP Database from the time of database creation to 1 August 2022. Two investigators independently screened the literature, extracted information, and assessed the RCTs' quality with the Cochrane Collaboration Network Risk of Bias 2.0. Network meta-analysis was performed using R language (X64 version 4.1.3) and STATA 17.0.ResultsWe identified 1,268 citations and of these included 38 trials comprising 3,412 participants. For improving dementia, the results of the network meta-analysis showed that compared with the control group (CON), PBM (SMD = 0.90, 95% CI: 0.43-1.37), EE (SMD = 0.71, 95% CI: 0.02-1.41), ET (SMD = 0.42, 95% CI: 0.16-0.68), and CST (SMD = 0.36, 95% CI: 0.11-0.62) were significantly different (P < 0.05); There was no significant difference in CCT (SMD = 0.41, 95% CI: -0.07-0.88) (P > 0.05). The ranked results showed that PBM has more potential to be the best intervention (P = 0.90). In addition, there was a significant difference between PBM and CST in improving cognitive function (SMD = 0.54, 95% CI: 0.00; 1.08, P < 0.05).ConclusionIn this study, NPTs have excellent potential to improve cognition in people with dementia, and PBM may have more significant benefits in improving cognition than the other four NPTs.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022363746.
| S-EPMC10035791 | biostudies-literature
Project description:BackgroundPositive health beliefs and attitudes towards dementia and dementia risk reduction may encourage adopting a healthy behaviour. Therefore, we aimed to investigate the knowledge, health beliefs and attitudes towards dementia and dementia risk reduction among the Dutch general population and its association with the intention to change health behaviours.MethodsA random sample of Dutch residents (30 to 80 years) was invited to complete an online survey. We collected data on knowledge, health beliefs and attitudes towards dementia (risk reduction) and the intention to change health behaviours. Multivariable logistic regression analyses were used to obtain effect estimates.ResultsSix hundred fifty-five participants completed the survey. In general, participants had insufficient knowledge about dementia and dementia risk reduction. Participants had relatively high scores on general health motivation and perceived benefits, but low scores on perceived susceptibility, perceived severity, perceived barriers, cues to action and self-efficacy. Individuals with higher scores on perceived benefits and cues to action had more often the intention to change their behaviour with regard to physical activity (OR = 1.33, 95%-CI:1.11-1.58; OR = 1.13, 95%-CI:1.03-1.24, respectively) and alcohol consumption (OR = 1.30, 95%-CI:1.00-1.69; OR = 1.17, 95%-CI:1.02-1.35, respectively). Younger excessive alcohol consumers with higher perceived severity scores had more often the intention to change their alcohol consumption behaviour (OR = 2.70, 95%-CI:1.04-6.97) compared to older excessive alcohol consumers. Opposite results were found for middle-aged excessive alcohol consumers (OR = 0.81, 95%-CI:0.67-0.99). Individuals who perceived more barriers had more often the intention to change their diet (OR = 1.10, 95%-CI:1.01-1.21), but less often the intention to change their smoking behaviour (OR = 0.78, 95%-CI:0.63-0.98). Moreover, less educated individuals with higher perceived benefits scores had less often the intention to change their diet (OR = 0.78, 95%-CI:0.60-0.99), while highly educated individuals with higher perceived benefits scores had more often the intention to change their diet (OR = 1.41, 95%-CI:1.12-1.78).ConclusionsThe knowledge, beliefs and attitudes towards dementia and dementia risk reduction among the Dutch general population is insufficient to support dementia risk reduction. More education about dementia and dementia risk reduction is needed to improve health beliefs and attitudes towards dementia and dementia risk reduction in order to change health behaviour.
| S-EPMC8094456 | biostudies-literature
Project description:Background The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results. Purpose To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and to determine definitively whether testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions. Methods We present the scientific and clinical rationale for the decisions made in the design of this set of trials. Results We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, common approaches to treatment and monitoring, and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data and safety monitoring board, the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in participant selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary outcomes for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation. Potential limitations Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one participant. Conclusion Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.
| S-EPMC4182174 | biostudies-literature
Project description:Phosphorylation is one of the most dynamic and widespread post-translational modifications regulating virtually every aspect of eukaryotic cell biology. Here, we assemble a dataset from 75 independent phosphoproteomic experiments performed in our laboratory using Saccharomyces cerevisiae. We report 30,902 phosphosites identified from cells cultured in a range of DNA damage conditions and/or arrested in distinct cell cycle stages. To generate a comprehensive resource for the budding yeast community, we aggregate our dataset with the Saccharomyces Genome Database and another recently published study, resulting in over 46,000 budding yeast phosphosites. With the goal of enhancing the identification of functional phosphorylation events, we perform computational positioning of phosphorylation sites on available 3D protein structures and systematically identify events predicted to regulate protein complex architecture. Results reveal hundreds of phosphorylation sites mapping to or near protein interaction interfaces, many of which result in steric or electrostatic "clashes" predicted to disrupt the interaction. With the advancement of Cryo-EM and the increasing number of available structures, our approach should help drive the functional and spatial exploration of the phosphoproteome.
| S-EPMC7857435 | biostudies-literature