Rates of cortical thinning in Alzheimer's disease signature regions associate with vascular burden but not with ß-amyloid status in cognitively normal adults at age 70.

BACKGROUND: Consistent patterns of reduced cortical thickness have been identified in early Alzheimer's disease (AD). However, the pathological factors that influence rates of cortical thinning within these AD signature regions remain unclear. METHODS: Participants were from the Insight 46 substudy of the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort), a prospective longitudinal cohort study. Linear regression was used to examine associations of baseline cerebral ß-amyloid (Aß) deposition, measured using florbetapir positron emission tomography, and baseline white matter hyperintensity volume (WMHV) on MRI, a marker of cerebral small vessel disease, with subsequent longitudinal changes in AD signature cortical thickness quantified from baseline and repeat MRI (mean [SD] interval 2.4 [0.2] years). RESULTS: In a population-based sample of 337 cognitively normal older white adults (mean [SD] age at baseline 70.5 [0.6] years; 48.1% female), higher global WMHV at baseline related to faster subsequent rates of cortical thinning in both AD signature regions (~0.15%/year faster per 10 mL additional WMHV), whereas baseline Aß status did not. Among Aß positive participants (n=56), there was some evidence that greater global Aß standardised uptake value ratio at baseline related to faster cortical thinning in the AD signature Mayo region, but this did not reach statistical significance (p=0.08). CONCLUSIONS: Cortical thinning within AD signature regions may develop via cerebrovascular pathways. Perhaps reflecting the age of the cohort and relatively low prevalence of Aß-positivity, robust Aß-related differences were not detected. Longitudinal follow-up incorporating additional biomarkers will allow assessment of how these relationships evolve closer to expected dementia onset.

Management of Malignant Bowel Obstruction: An Innovative Proactive Outpatient Nurse-Led Model of Care for Patients With Advanced Gynecologic Cancer.

BACKGROUND: Malignant bowel obstruction (MBO) in patients with advanced gynecologic cancer (GyCa) can negatively impact clinical outcomes and quality of life. Oncology nurses can support these patients with adequate tools/processes. PROBLEM: Patients with GyCa with/at risk of MBO endure frequent emergency or hospital admissions, impacting patient care. APPROACH: Optimizing oncology nurses' role to improve care for patients with GyCa with/at risk of MBO, the gynecology oncology interprofessional team collaborated to develop a proactive outpatient nurse-led MBO model of care (MOC). OUTCOMES: The MBO MOC involves a risk-based algorithm engaging interdisciplinary care, utilizing standardized tools, risk-based assessment, management, and education for patients and nurses. The MOC has improved patient-reported confidence level of bowel self-management and decreased hospitalization. Following education, nurses demonstrated increased knowledge in MBO management. CONCLUSIONS: An outpatient nurse-led MBO MOC can improve patient care and may be extended to other cancer centers, fostering collaboration and best practice.

Population-based blood screening for preclinical Alzheimer's disease in a British birth cohort at age 70.

Alzheimer's disease has a preclinical stage when cerebral amyloid-ß deposition occurs before symptoms emerge, and when amyloid-ß-targeted therapies may have maximum benefits. Existing amyloid-ß status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for screening. We compared three different blood-based techniques-liquid chromatography-mass spectrometry measures of plasma amyloid-ß, and single molecule array (Simoa) measures of plasma amyloid-ß and phospho-tau181-to detect cortical 18F-florbetapir amyloid PET positivity (defined as a standardized uptake value ratio of >0.61 between a predefined cortical region of interest and eroded subcortical white matter) in dementia-free members of Insight 46, a substudy of the population-based British 1946 birth cohort. We used logistic regression models with blood biomarkers as predictors of amyloid PET status, with or without age, sex and APOE ε4 carrier status as covariates. We generated receiver operating characteristics curves and quantified areas under the curves to compare the concordance of the different blood tests with amyloid PET. We determined blood test cut-off points using Youden's index, then estimated numbers needed to screen to obtain 100 amyloid PET-positive individuals. Of the 502 individuals assessed, 441 dementia-free individuals with complete data were included; 82 (18.6%) were amyloid PET-positive. The area under the curve for amyloid PET status using a base model comprising age, sex and APOE ε4 carrier status was 0.695 (95% confidence interval: 0.628-0.762). The two best-performing Simoa plasma biomarkers were amyloid-ß42/40 (0.620; 0.548-0.691) and phospho-tau181 (0.707; 0.646-0.768), but neither outperformed the base model. Mass spectrometry plasma measures performed significantly better than any other measure (amyloid-ß1-42/1-40: 0.817; 0.770-0.864 and amyloid-ß composite: 0.820; 0.775-0.866). At a cut-off point of 0.095, mass spectrometry measures of amyloid-ß1-42/1-40 detected amyloid PET positivity with 86.6% sensitivity and 71.9% specificity. Without screening, to obtain 100 PET-positive individuals from a population with similar amyloid PET positivity prevalence to Insight 46, 543 PET scans would need to be performed. Screening using age, sex and APOE ε4 status would require 940 individuals, of whom 266 would proceed to scan. Using mass spectrometry amyloid-ß1-42/1-40 alone would reduce these numbers to 623 individuals and 243 individuals, respectively. Across a theoretical range of amyloid PET positivity prevalence of 10-50%, mass spectrometry measures of amyloid-ß1-42/1-40 would consistently reduce the numbers proceeding to scans, with greater cost savings demonstrated at lower prevalence.

Subjective cognitive complaints at age 70: associations with amyloid and mental health.

OBJECTIVE: To investigate subjective cognitive decline (SCD) in relation to ß-amyloid pathology and to test for associations with anxiety, depression, objective cognition and family history of dementia in the Insight 46 study. METHODS: Cognitively unimpaired ~70-year-old participants, all born in the same week in 1946 (n=460, 49% female, 18% amyloid-positive), underwent assessments including the SCD-Questionnaire (MyCog). MyCog scores were evaluated with respect to 18F-Florbetapir-PET amyloid status (positive/negative). Associations with anxiety, depression, objective cognition (measured by the Preclinical Alzheimer Cognitive Composite, PACC) and family history of dementia were also investigated. The informant's perspective on SCD was evaluated in relation to MyCog score. RESULTS: Anxiety (mean (SD) trait anxiety score: 4.4 (3.9)) was associated with higher MyCog scores, especially in women. MyCog scores were higher in amyloid-positive compared with amyloid-negative individuals (adjusted means (95% CIs): 5.3 (4.4 to 6.1) vs 4.3 (3.9 to 4.7), p=0.044), after accounting for differences in anxiety. PACC (mean (SD) -0.05 (0.68)) and family history of dementia (prevalence: 23.9%) were not independently associated with MyCog scores. The informant's perception of SCD was generally in accordance with that of the participant. CONCLUSIONS: This cross-sectional study demonstrates that symptoms of SCD are associated with both ß-amyloid pathology, and more consistently, trait anxiety in a population-based cohort of older adults, at an age when those who are destined to develop dementia are still likely to be some years away from symptoms. This highlights the necessity of considering anxiety symptoms when assessing Alzheimer's disease pathology and SCD.

Mild Parkinsonian Signs: A Systematic Review of Clinical, Imaging, and Pathological Associations.

Mild parkinsonian signs (MPS) have been widely studied during the past 3 decades and proposed as a risk marker for neurodegenerative disease. This systematic review explores the epidemiology, clinical and prognostic associations, radiological features, and pathological findings associated with MPS in older adults free from neurodegenerative disease. We find that MPS as currently defined are strongly associated with increasing age and increased risk of development of Parkinson's disease (PD), all-cause dementia, disability, and death. Positive associations with later PD are found mainly in younger populations and those with other features of prodromal PD. There are currently no consistent radiological findings for MPS, and pathological studies have shown that MPS, at least in the oldest old, are often underpinned by mixed neuropathologies, including those associated with Alzheimer's disease, cerebrovascular disease, nigral neuronal loss, and Lewy bodies. Different subcategories of MPS appear to convey varying risk and specificity for PD and other outcomes. MPS overall are not specific for parkinsonian disorders and, although associated with increased risk of PD, can reflect multiple pathologies, particularly in older individuals. "Mild motor signs" appears a more appropriate term to avoid prognostic and pathological implications, and larger future studies to prospectively examine outcomes and associations of specific MPS subcategories are required. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Diet quality in late midlife is associated with faster walking speed in later life in women, but not men: findings from a prospective British birth cohort.

Healthy diet has been linked to better age-related functioning, but evidence on the relationship of diet quality in late midlife and measures of physical capability in later life is limited. Research on potential sex differences in this relationship is scarce. The aim was to investigate the prospective association between overall diet quality, as assessed by the Healthy Eating Index-2015 (HEI-2015) at 60-64 years and measures of walking speed 7 years later, among men and women from the Insight 46, a neuroscience sub-study of the Medical Research Council National Survey of Health and Development. Diet was assessed at 60-64 years using 5-d food diaries, from which total HEI-2015 was calculated. At 69-71 years, walking speed was estimated during four 10-m walks at self-selected pace, using inertial measurement units. Multivariable linear regression models with sex as a modifier, controlling for age, follow-up, lifestyle, health/social variables and physical performance, were used. The final sample consists of 164 women and 167 men (n 331). Women had higher HEI-2015 and slower walking speed than men. A 10-point increase in HEI-2015 was associated with faster walking speed among women (B 0·024, 95 % CI 0·006, 0·043), but not men. The association remained significant in the multivariable model (B 0·021, 95 % CI 0·003, 0·040). In women, higher diet quality in late midlife is associated with faster walking speed. A healthy diet in late midlife is likely to contribute towards better age-related physical capability, and sex differences are likely to affect this relationship.

Allostatic load and ageing: linking the microbiome and nutrition with age-related health.

Ageing is a process of decline in physiological function and capability over time. It is an anticipated major burden on societal health-care costs due to an increasingly aged global population. Accelerated biological ageing is a feature of age-related morbidities, which also appear to share common underpinning features, including low-grade persistent inflammation, phosphate toxicity, diminished Nrf2 activity, a depleted metabolic capability, depressed mitochondrial biogenesis and a low diversity gut microbiome.Social, psychological, lifestyle and nutritional risk factors can all influence the trajectory of age-related health, as part of an individual's exposome, which reflects the interplay between the genome and the environment. This is manifest as allostatic (over)load reflecting the burden of lifestyle/disease at both a physiological and molecular level. In particular, age-related genomic methylation levels and inflammatory status reflect exposome differences. These features may be mediated by changes in microbial diversity. This can drive the generation of pro-inflammatory factors, such as TMAO, implicated in the 'diseasome' of ageing. Additionally, it can be influenced by the 'foodome', via nutritional differences affecting the availability of methyl donors required for maintenance of the epigenome and by the provision of nutritionally derived Nrf2 agonists. Both these factors influence age-related physiological resilience and health. This offers novel insights into possible interventions to improve health span, including a rage of emerging senotherapies and simple modifications of the nutritional and environmental exposome. In essence, the emerging strategy is to treat ageing processes common to the diseasome of ageing itself and thus preempt the development or progression of a range of age-related morbidities.

Methyl Donor Nutrients in Chronic Kidney Disease: Impact on the Epigenetic Landscape.

Epigenetic alterations, such as those linked to DNA methylation, may potentially provide molecular explanations for complications associated with altered gene expression in illnesses, such as chronic kidney disease (CKD). Although both DNA hypo- and hypermethylation have been observed in the uremic milieu, this remains only a single aspect of the epigenetic landscape and, thus, of any biochemical dysregulation associated with CKD. Nevertheless, the role of uremia-promoting alterations on the epigenetic landscape regulating gene expression is still a novel and scarcely studied field. Although few studies have actually reported alterations of DNA methylation via methyl donor nutrient intake, emerging evidence indicates that nutritional modification of the microbiome can affect one-carbon metabolism and the capacity to methylate the genome in CKD. In this review, we discuss the nutritional modifications that may affect one-carbon metabolism and the possible impact of methyl donor nutrients on the microbiome, CKD, and its phenotype.

Planned early birth versus expectant management for women with preterm prelabour rupture of membranes prior to 37 weeks' gestation for improving pregnancy outcome.

BACKGROUND: Current management of preterm prelabour rupture of the membranes (PPROM) involves either initiating birth soon after PPROM or, alternatively, adopting a 'wait and see' approach (expectant management). It is unclear which strategy is most beneficial for mothers and their babies. This is an update of a Cochrane review published in 2010 (Buchanan 2010). OBJECTIVES: To assess the effect of planned early birth versus expectant management for women with preterm prelabour rupture of the membranes between 24 and 37 weeks' gestation for fetal, infant and maternal well being. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (30 September 2016), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials comparing planned early birth with expectant management for women with PPROM prior to 37 weeks' gestation. We excluded quasi-randomised trials. DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated trials for inclusion into the review and for methodological quality. Two review authors independently extracted data. We checked data for accuracy. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We included 12 trials in the review (3617 women and 3628 babies). For primary outcomes, we identified no clear differences between early birth and expectant management in neonatal sepsis (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.66 to 1.30, 12 trials, 3628 babies, evidence graded moderate), or proven neonatal infection with positive blood culture (RR 1.24, 95% CI 0.70 to 2.21, seven trials, 2925 babies). However, early birth increased the incidence of respiratory distress syndrome (RDS) (RR 1.26, 95% CI 1.05 to 1.53, 12 trials, 3622 babies, evidence graded high). Early birth was also associated with an increased rate of caesarean section (RR 1.26, 95% CI 1.11 to 1.44, 12 trials, 3620 women, evidence graded high).Assessment of secondary perinatal outcomes showed no clear differences in overall perinatal mortality (RR 1.76, 95% CI 0.89 to 3.50, 11 trials, 3319 babies), or intrauterine deaths (RR 0.45, 95% CI 0.13 to 1.57, 11 trials, 3321 babies) when comparing early birth with expectant management. However, early birth was associated with a higher rate of neonatal death (RR 2.55, 95% CI 1.17 to 5.56, 11 trials, 3316 babies) and need for ventilation (RR 1.27, 95% CI 1.02 to 1.58, seven trials, 2895 babies, evidence graded high). Babies of women randomised to early birth were delivered at a gestational age lower than those randomised to expectant management (mean difference (MD) -0.48 weeks, 95% CI -0.57 to -0.39, eight trials, 3139 babies). Admission to neonatal intensive care was more likely for those babies randomised to early birth (RR 1.16, 95% CI 1.08 to 1.24, four trials, 2691 babies, evidence graded moderate).In assessing secondary maternal outcomes, we found that early birth was associated with a decreased rate of chorioamnionitis (RR 0.50, 95% CI 0.26 to 0.95, eight trials, 1358 women, evidence graded moderate), and an increased rate of endometritis (RR 1.61, 95% CI 1.00 to 2.59, seven trials, 2980 women). As expected due to the intervention, women randomised to early birth had a higher chance of having an induction of labour (RR 2.18, 95% CI 2.01 to 2.36, four trials, 2691 women). Women randomised to early birth had a decreased total length of hospitalisation (MD -1.75 days, 95% CI -2.45 to -1.05, six trials, 2848 women, evidence graded moderate).Subgroup analyses indicated improved maternal and infant outcomes in expectant management in pregnancies greater than 34 weeks' gestation, specifically relating to RDS and maternal infections. The use of prophylactic antibiotics were shown to be effective in reducing maternal infections in women randomised to expectant management.Overall, we assessed all 12 studies as being at low or unclear risk of bias. Some studies lacked an adequate description of methods and the risk of bias could only be assessed as unclear. In five of the studies there were one and/or two domains where the risk of bias was judged as high. GRADE profiling showed the quality of evidence across all critical outcomes to be moderate to high. AUTHORS' CONCLUSIONS: With the addition of five randomised controlled trials (2927 women) to this updated review, we found no clinically important difference in the incidence of neonatal sepsis between women who birth immediately and those managed expectantly in PPROM prior to 37 weeks' gestation. Early planned birth was associated with an increase in the incidence of neonatal RDS, need for ventilation, neonatal mortality, endometritis, admission to neonatal intensive care, and the likelihood of birth by caesarean section, but a decreased incidence of chorioamnionitis. Women randomised to early birth also had an increased risk of labour induction, but a decreased length of hospital stay. Babies of women randomised to early birth were more likely to be born at a lower gestational age.In women with PPROM before 37 weeks' gestation with no contraindications to continuing the pregnancy, a policy of expectant management with careful monitoring was associated with better outcomes for the mother and baby.The direction of future research should be aimed at determining which groups of women with PPROM would not benefit from expectant management. This could be determined by analysing subgroups according to gestational age at presentation, corticosteroid usage, and abnormal vaginal microbiological colonisation. Research should also evaluate long-term neurodevelopmental outcomes of infants.