Alzheimer’s disease genetic risk and cognitive reserve in relationship to long-term cognitive trajectories among cognitively normal individuals

Background: Both Alzheimer’s disease (AD) genetic risk factors and indices of cognitive reserve (CR) influence risk of cognitive decline, but it remains unclear whether they interact. This study examined whether a CR index score modifies the relationship between AD genetic risk factors and long-term cognitive trajectories in a large sample of individuals with normal cognition. Methods: Analyses used data from the Preclinical AD Consortium, including harmonized data from 5 longitudinal cohort studies. Participants were cognitively normal at baseline (M baseline age = 64 years, 59% female) and underwent 10 years of follow-up, on average. AD genetic risk was measured by (i) apolipoprotein-E (APOE) genetic status (APOE-ε2 and APOE-ε4 vs. APOE-ε3; N = 1819) and (ii) AD polygenic risk scores (AD-PRS; N = 1175). A CR index was calculated by combining years of education and literacy scores. Longitudinal cognitive performance was measured by harmonized factor scores for global cognition, episodic memory, and executive function. Results: In mixed-effects models, higher CR index scores were associated with better baseline cognitive performance for all cognitive outcomes. APOE-ε4 genotype and AD-PRS that included the APOE region (AD-PRSAPOE) were associated with declines in all cognitive domains, whereas AD-PRS that excluded the APOE region (AD-PRSw/oAPOE) was associated with declines in executive function and global cognition, but not memory. There were significant 3-way CR index score × APOE-ε4 × time interactions for the global (p = 0.04, effect size = 0.16) and memory scores (p = 0.01, effect size = 0.22), indicating the negative effect of APOE-ε4 genotype on global and episodic memory score change was attenuated among individuals with higher CR index scores. In contrast, levels of CR did not attenuate APOE-ε4-related declines in executive function or declines associated with higher AD-PRS. APOE-ε2 genotype was unrelated to cognition. Conclusions: These results suggest that APOE-ε4 and non-APOE-ε4 AD polygenic risk are independently associated with global cognitive and executive function declines among individuals with normal cognition at baseline, but only APOE-ε4 is associated with declines in episodic memory. Importantly, higher levels of CR may mitigate APOE-ε4-related declines in some cognitive domains. Future research is needed to address study limitations, including generalizability due to cohort demographic characteristics

The astrobiology primer: An outline of general knowledge - Version 1, 2006

Peer reviewe

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Update to the effectiveness and cost-effectiveness of a mindfulness training programme in schools compared with normal school provision (MYRIAD): study protocol for a randomised controlled trial

Abstract: Background: MYRIAD (My Resilience in Adolescence) is a superiority, parallel group, cluster randomised controlled trial designed to examine the effectiveness and cost-effectiveness of a mindfulness training (MT) programme, compared with normal social and emotional learning (SEL) school provision to enhance mental health, social-emotional-behavioural functioning and well-being in adolescence. The original trial protocol was published in Trials (accessible at https://doi.org/10.1186/s13063-017-1917-4). This included recruitment in two cohorts, enabling the learning from the smaller first cohort to be incorporated in the second cohort. Here we describe final amendments to the study protocol and discuss their underlying rationale. Methods: Four major changes were introduced into the study protocol: (1) there were changes in eligibility criteria, including a clearer operational definition to assess the degree of SEL implementation in schools, and also new criteria to avoid experimental contamination; (2) the number of schools and pupils that had to be recruited was increased based on what we learned in the first cohort; (3) some changes were made to the secondary outcome measures to improve their validity and ability to measure constructs of interest and to reduce the burden on school staff; and (4) the current Coronavirus Disease 2019 (SARS-CoV-2 or COVID-19) pandemic both influences and makes it difficult to interpret the 2-year follow-up primary endpoint results, so we changed our primary endpoint to 1-year follow-up. Discussion: These changes to the study protocol were approved by the Trial Management Group, Trial Steering Committee and Data and Ethics Monitoring Committees and improved the enrolment of participants and quality of measures. Furthermore, the change in the primary endpoint will give a more reliable answer to our primary question because it was collected prior to the COVID-19 pandemic in both cohort 1 and cohort 2. Nevertheless, the longer 2-year follow-up data will still be acquired, although this time-point will be now framed as a second major investigation to answer some new important questions presented by the combination of the pandemic and our study design. Trial registration: International Standard Randomised Controlled Trials ISRCTN86619085. Registered on 3 June 2016

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders

Background People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. Results We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson’s disease (and none with Alzheimer’s disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights. Conclusions We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences