The present study aims to investigate the current trends in replacing conventional preservatives with multifunctional ingredients with antimicrobial properties for preservation of cosmetics for infants or sensitive population, to decrease their potential for contact dermatitis. We first reviewed the labels of cosmetics purchased from the Chinese market for conventional preservatives and multifunctional ingredients with antimicrobial properties, of which the actual contents were further quantified by chromatographic methods. We identified 7 traditional preservatives (phenoxyethanol, benzoic acid (salts), methylparaben, benzyl alcohol, sorbic acid (salts), propylparaben, and methylisothiazolinone), and 11 alternative ingredients with antimicrobial activities (ethylhexylglycerin, butylene glycol, caprylyl glycol, propylene glycol, 1,2-hexanediol, p-anisic acid, hydroxyacetophenone, pentylene glycol, decylene glycol, caprylhydroxamic acid, and aminomethyl propanol) in descending order of prevalence. The contents of all identified preservatives and ingredients were either below regulatory limits or in the range that is generally regarded to be safe. Further challenge with microorganisms indicated irrespective of the composition of preservation systems, product preservation could be compromised under test conditions. We conclude that multifunctional ingredients with antimicrobial properties in cosmetics have the potential to completely replace or significantly reduce the use of traditional preservatives while retaining comparative preservative efficacy. Future attentions may need to be shifted to the safety of those multifunctional ingredients with antimicrobial properties.

BACKGROUND: Accelerated Long-term Forgetting (ALF) is the phenomenon whereby material is retained normally over short intervals (minutes or hours) but forgotten abnormally rapidly over longer periods (days or weeks). ALF may be an early marker of cognitive decline, but little is known about its relationships with preclinical Alzheimer\'s disease pathology in older adults, and how memory selectivity may influence which material is forgotten.
METHODS: Participants in \'Insight 46\', a sub-study of the MRC National Survey of Health and Development (British 1946 birth cohort), completed cognitive and neuroimaging assessments at two time-points (baseline at age ∼70; follow-up ∼2.4 years later). At follow-up, we assessed Complex Figure Drawing (copy; immediate recall; 30-minute recall; 7-day recall). Complex Figure items were categorized as \'outline\' or \'detail\' (Fig1), to test the hypothesis that forgetting the outline of the structure would be more sensitive to the effect of brain pathologies. ALF scores were calculated as the proportion of material retained after 7 days, relative to 30 minutes. Rates of cerebral atrophy between baseline and follow-up were quantified from T1-weighted MRI using the Brain Boundary Shift Integral (BBSI). β-amyloid status (positive/negative) was determined from 18F-Florbetapir-PET. Baseline serum neurofilament light (NfL) was quantified (Quanterix Simoa assay). Multivariable regression models were used to investigate the effects (mutually adjusted) of β-amyloid status, BBSI and NfL on ALF in n = 316 clinically-normal individuals (50% female; 22% β-amyloid positive; 30% APOE-ε4 carriers), and to explore interactions between these predictors, adjusting for potential confounders including prospectively-collected childhood cognitive ability and education.
RESULTS: \'Outline\' items were better retained than \'detail\' (Fig1). β-amyloid-positive participants had poorer ALF scores for \'outline\' (but not \'detail\') items (Fig1C; Table 1). Unexpectedly, higher NfL was associated with scores for \'outline\' items (Table 1). Greater rate of cerebral atrophy predicted poorer retention among participants with elevated β-amyloid and higher NfL (Table 1; Fig2).
CONCLUSIONS: These results provide evidence of associations between biomarkers of brain pathologies and ALF in 73-year-olds. Interactions between different biomarkers merit further exploration. ALF may be a sensitive outcome measure for therapeutic trials in preclinical AD. Better retention of \'outline\' (vs. \'detail\') items illustrates the strategic role of memory selectivity.

BACKGROUND: In the present study, we investigated differences in amyloid (Aβ) burden and personality traits in cognitively-select older adults compared to average-functioning older adults. Conscientiousness, in particular, has been linked to Alzheimer\'s Disease (AD) pathology, and we hypothesized that adults who were high in cognition would exhibit enhanced conscientiousness. Of additional interest was whether high functioning older adults in the Dallas Lifespan Brain Study would evidence reduced AD pathology.
METHODS: We tested 285 cognitively-normal participants (ages 55-90) and collected conscientiousness scores using the Revised NEO Personality Inventory (NEO-PI-R). Participants also underwent PET imaging with radiotracer AV-45, 18F-Florbetapir, a radiotracer that is used to measure Aβ protein in the brain. Mean cortical SUVR was computed across 8 cortical regions of interest, normalized to cerebellar gray matter. In addition, participants completed a cognitive battery, underwent an MRI scan, and completed self-reports for depression and fitness. We designated those participants scoring at or above the mean episodic memory of a middle-aged (ages 35-54) reference group, as \"cognitively-select\" (N = 69), and those scoring below the mean, as \"cognitively-normal\" (N = 216). Dependent variables of interest included global and regional amyloid (Aβ), cortical morphometry, depression, fitness, conscientiousness, and various cognitive measures.
RESULTS: Cognitively select participants were younger (p = .043), more educated (p = .021), and had higher positive personality traits, including self-discipline (p = .01), openness to ideas (p = .013), and competence (p = .015), compared to cognitively-normal. Although the groups did not differ in global Aβ pathology load (p = .083), cognitively select exhibited less pathology in specific regions including lateral temporal areas (p = .049). Regression analysis controlling for sex, age, education, and MMSE, revealed a significant group by global Aβ interaction on fluid ability (p = .034), where greater Aβ load predicted lower scores in cognitively normal older adults only.
CONCLUSIONS: These findings provide evidence that cognitively privileged adults show resistance to decline across many domains and demonstrate resilience to amyloid pathology. Discussion will focus on longitudinal change in amyloid accumulation, cortical thinning, and cognitive decline, as well as the concept of reserve.

OBJECTIVE: Twin-screw wet granulation (TSWG) is a manufacturing process that offers several advantages for the processing of water-insoluble active pharmaceutical ingredients (APIs) and has been used for increasing the solubility and dissolution rates. Here we introduce a novel TSWG approach with reduced downstream processing steps by using non-volatile solvents as granulating binders.
METHODS: Herein, TSWG was carried out using Transcutol a non-volatile protic solvent as a granulating binder and dissolution enhancer of ibuprofen (IBU) blends with cellulose polymer grades (Pharmacoat® 603, Affinisol™, and AQOAT®).
RESULTS: The physicochemical characterisation of the produced granules showed excellent powder flow and the complete transformation of IBU into the amorphous state. Dissolution studies presented immediate release rates for all IBU formulations due to the high drug-polymer miscibility and the Transcutol solubilising capacity.
CONCLUSIONS: Overall, the study demonstrated an innovative approach for the development of extruded granules by processing water-insoluble APIs with non-volatile solvents for enhanced dissolution rates at high drug loadings.

BACKGROUND: Declining ability to independently perform instrumental activities of daily living (IADL) is a hallmark of early-stage Alzheimer\'s disease (AD). Financial capacity, an aspect of IADL, includes financial skills such as balancing a checkbook and making change and is potentially sensitive to early decline in cognitive abilities, raising the question of how financial capacity is affected by buildup of cerebral tau and amyloid-hallmarks of AD pathology.
OBJECTIVE: This study aimed to examine the relationship between cerebral tau, amyloid, and their interaction with change in financial capacity over time.
METHODS: Participants were selected from the Alzheimer\'s Disease Neuroimaging Initiative (ADNI) to have at least one yearly follow-up Financial Capacity Instrument-Short Form (FCI-SF) exam and a flortaucipir (tau) PET scan within 6 months of baseline (and in a subset, a florbetapir (amyloid) PET scan within a year of baseline).
METHODS: Multi-center international cohort study.
METHODS: Sample size was 507-322 cognitively normal (CN) and 185 with amnestic mild cognitive impairment (MCI). Sixty-two percent (N=316) had amyloid data.
METHODS: Linear mixed-effects models predicted FCI-SF total score from baseline tau, age, gender, premorbid intelligence, executive function, memory, and the interaction of each with time. Regions of interest included inferior temporal, entorhinal cortex, precuneus, posterior cingulate, supramarginal, and dorsolateral prefrontal (DLPF). Additional models examined amyloid and its interaction with tau. Results were adjusted for multiple comparisons.
RESULTS: Among the whole sample and in CN participants alone, higher baseline tau in all regions, most prominently in the inferior temporal, entorhinal cortex, and supramarginal regions, was significantly associated with worse performance on the FCI-SF over time. Among MCI participants alone, this relationship was significant in the entorhinal cortex (unstandardized b = 0.27, t = 3.71, adjusted p = 0.001), inferior temporal (b = 0.27, t = 3.96, p < 0.001), precuneus (b = 0.27, t = 3.04, p = 0.01), and supramarginal (b = 0.27, t = 2.74, p = 0.02) regions. Amyloid alone was significantly associated with worse FCI-SF performance in only the whole sample (b = 0.15, t = 2.37, p = 0.04), and a three-way interaction between tau, amyloid, and time was only present for entorhinal cortex tau in CN individuals (b = -1.61, t = -2.61, p = 0.03).
CONCLUSIONS: Early tau accumulation is linked to worsening financial capacity over time in CN older adults and MCI. Declining financial capacity may signal pathological buildup and serve as an early warning sign for AD, and future research should continue to investigate the longitudinal relationship between tau, financial capacity, and other IADL.

BACKGROUND: Preclinical Alzheimer\'s disease is increasingly studied in clinical trials. Although safety signals are routinely monitored in clinical trial populations with Alzheimer\'s disease, it can be challenging to identify new safety signals against background rates of age-related medical comorbidities.
OBJECTIVE: To report detailed safety data from a cognitively unimpaired older population with evidence of elevated cerebral amyloid levels on amyloid positron emission tomography in the placebo arm of a Phase 3 clinical trial.
METHODS: Phase 3, 4.5-year, multicenter, placebo-controlled trial.
METHODS: Placebo data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer\'s Disease (A4) study.
METHODS: Enrolled participants were aged 65-85 years with a global Clinical Dementia Rating score of 0, a Mini-Mental State Examination score of 25-30, a Wechsler Memory Scale Logical Memory IIa (delayed recall) score of 6-18, and elevated brain amyloid levels on 18F-florbetapir positron emission tomography.
METHODS: Study participants who received placebo were followed up with post-baseline safety measures. Assessments included review of concomitant medication and adverse events, the Columbia Suicide Severity Rating Scale, electrocardiograms, and neuroimaging (brain magnetic resonance imaging).
RESULTS: In total, 591 study participants (mean age [standard deviation] 71.9 [5.0] years) were assigned to and received placebo in the A4 study, and were followed up to 240 weeks. Participants were primarily White (93.9%) and from the United States (86.8%); 60.4% were women. The most common serious adverse events (incidence rate per 100 person-years) were pneumonia (incidence rate=0.4; 95% confidence interval=0.2-0.7) and atrial fibrillation (incidence rate=0.4; 95% confidence interval=0.2-0.7). The most common treatment-emergent adverse events were upper respiratory tract infection (incidence rate=10.9; 95% confidence interval=9.4-12.5), fall (incidence rate=7.7; 95% confidence interval=6.6-9.0), and nasopharyngitis (incidence rate=5.8; 95% confidence interval=4.8-6.9). The most common ischemia-related findings on magnetic resonance imaging were subcortical infarction (incidence rate=1.4; 95% confidence interval=1.0-2.0) and acute ischemia (incidence rate=0.6; 95% confidence interval=0.3-1.0). Emergent amyloid-related imaging abnormalities with hemosiderin deposition occurred in 32.8% of participants who received placebo; the primary factor associated with these events during the post-baseline period was the number of microhemorrhages at baseline (odds ratio=349.9; 95% confidence interval=247.6-494.4; adjusted p<0.001).
CONCLUSIONS: Safety findings in the placebo-treated group from the A4 study provide a robust characterization of expected safety in a clinical trial population with preclinical Alzheimer\'s disease. These results may provide context in planning future studies and safety evaluations during ongoing blinded studies in preclinical Alzheimer\'s disease.

BACKGROUND: The Anti-Amyloid in Asymptomatic Alzheimer\'s Disease (A4) Study failed to show a treatment benefit with solanezumab, but the longitudinal consequences of elevated amyloid were observed in study participants with objective decline on the Preclinical Alzheimer Cognitive Composite (PACC) and subjective decline on the combined Cognitive Function Index (participant + study partner CFI), during the trial period.
OBJECTIVE: We sought to expand on previous findings by comparing longitudinal patterns of participant and study partner CFI separately and their associations with the PACC stratified by baseline amyloid tertile over the course of the A4 Study.
METHODS: Cognitively unimpaired older adult participants and their study partners were independently administered the CFI at screen prior to amyloid PET disclosure and then at 3 subsequent visits (week 48, week 168, week 240) of the study. PACC collected at visits concurrent with CFI administration were also examined longitudinally.
METHODS: The A4 Study was conducted at 67 sites in Australia, Canada, Japan, and the United States.
METHODS: 1,147 participants with elevated amyloid based on florbetapir PET were enrolled in the A4 Study and included in these analyses. 583 were on placebo and 564 were treated with solanezumab.
METHODS: The PACC was used to assess objective cognitive performance and the CFI was used to assess change in everyday cognitive functioning by the participant and their study partner independently. Amyloid level was characterized by Centiloid tertiles (<46.1 CL, 46.1 to 77.2 CL, >77.2 CL). Participants were aware of their elevated amyloid status, but not their CL tertile, or specific level of amyloid. Longitudinal correlations between participant and study partner CFI and PACC were examined at all visits where assessments were available. The impact of baseline amyloid tertile on CFI and PACC associations was also examined.
RESULTS: Both participant and study partner CFI increased over the duration of the study indicating worsening cognitive functioning. Results did not differ by treatment group. The association between higher CFI and worse PACC for both for participant and study partner became progressively stronger over the course of the study. PACC had a significantly higher correlation with study partner CFI than with participant CFI by week 168. The stronger correlations between study partner CFI and PACC were driven by those in the highest amyloid tertile.
CONCLUSIONS: Both participant and study partner report captured subtle changes in everyday cognitive functioning for participants with biomarker confirmed and disclosed preclinical AD. Moreover, study partner report was most highly aligned with cognitive decline, particularly among those with the highest amyloid load.

BACKGROUND: Individuals from diverse racial and ethnic groups are severely underrepresented in Alzheimer\'s disease trials in part due to disproportionate biomarker ineligibility. Evidence from recent studies support plasma phosphorylated tau 217 (P-tau217) as an early marker for brain Aβ pathology and a reliable marker in predicting elevated brain amyloid PET in cognitively unimpaired adults.
OBJECTIVE: To examine whether the relationship between P-tau217 and 18-F florbetapir PET standard uptake value ratios (SUVR) is influenced by race and ethnicity in the Anti-Amyloid treatment in Asymptomatic Alzheimer\'s disease (A4) preclinical AD studies.
METHODS: We conducted a retrospective analysis of A4 clinical trial and the LEARN natural history companion study data to evaluate the relationship between baseline P-tau217 and PET SUVR concentration levels by race and ethnicity.
METHODS: The analysis was conducted on samples from participants enrolled across 65 study sites in the United States and Canada.
METHODS: Cognitively unimpaired adults aged 65-85 enrolled at North American sites in the A4 preclinical AD trial, pre-dose, (N=1018), and the LEARN (N=480) study. Participants were grouped into 2 categories, racial and ethnic underrepresented group (RE-URG) and non-RE-URG (nRE-URG) based on self-identification.
METHODS: A mixed-effects regression model was fit to determine differences in the relationship between P-tau217 and PET SUVR by race and ethnicity, adjusting for age, and APOE ε4 carrier status.
RESULTS: Results from the linear mixed-effects model support that there was no statistically significant effect of race and ethnicity on the relationship between P-tau217 and PET SUVR.
CONCLUSIONS: These findings suggest that the relationship between plasma P-tau217 and PET SUVR is the same across race and ethnicity. Future analyses should corroborate these findings in a larger sample and examine whether plasma P-tau217 reflects the differential amyloid prevalence previously reported for other biomarkers of amyloid.

BACKGROUND: Clinical Dementia Rating (CDR) global (CDR-G) and sum of box scores (CDR-SB) are commonly used as primary outcome variables to measure progression or treatment effects in symptomatic Alzheimer disease (AD) clinical trials.
OBJECTIVE: We sought to determine whether the CDR is sensitive to change in pre-symptomatic AD and whether there are specific CDR boxes that are dynamic during the multi-year Anti-Amyloid in Asymptomatic Alzheimer\'s Disease (A4) secondary prevention study.
METHODS: All participants entered the study with a CDR-G of 0. Box scores were examined individually and as composites of cognition (memory, orientation and judgment /problem solving) and function (community affairs and home/ hobbies). A progression in box score was tabulated only when the change occurred at two consecutive visits.
METHODS: The A4 study took place at 67 sites in Australia, Canada, Japan and the United States.
METHODS: 1,147 individuals, ages 65-85, were randomized to either placebo (n= 583) or solanezumab (n= 564). All participants received a baseline flobetapir PET scan, an annual CDR, and cognitive testing every 6 months with the Primary Alzheimer Cognitive Composite (PACC) over the course of 240 weeks.
METHODS: Generalized estimating equations and generalized least square models were used to explore the modeled mean progression rate in the CDR-G, CDR-SB, individual CDR boxes, and CDR composite scores in the combined solanezumab and placebo groups. Models were refitted to explore the probability of CDR progression in centiloid tertiles of amyloid at baseline (< 46.1 CL, 46.1 to 77.2 CL, > 77.2 CL). All models included effects for age, education, APOEε4 carrier status, baseline amyloid with flobetapir PET, treatment, and time-by-treatment.
RESULTS: There were no statistical differences between the placebo or solanezumab groups in CDR-G, CDR-SB, specific CDR boxes or CDR composite scores over the course of the trial. Changes in judgment/ problem solving were present at baseline and persisted over time, but progression on the CDR memory box and the CDR cognitive composite quickly predominated. Community affairs and home/ hobbies showed little progression. Personal care remained stable. The probability of cognitive and functional progression in CDR boxes began either at the intermediate or advanced amyloid level (46.1 to 77.2 CL, > 77.2 CL), while amyloid at the lowest level (< 46.1 CL) showed relatively little CDR progression.
CONCLUSIONS: The findings suggest that the CDR memory box and the CDR cognitive composite progressed over 240 weeks and were associated with intermediate and advanced stages of amyloid at baseline. Functional changes in community affairs and home/hobbies were relatively stable. These finding suggest that specific CDR box score changes may help refine our measurement of expected treatment effects in future AD prevention trials.

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