Among cognitively normal individuals, elevated brain amyloid (defined by cerebrospinal fluid assays or positron emission tomography regional summaries) can be related to risk for later ...Alzheimer-related cognitive decline.
To characterize and quantify the risk for Alzheimer-related cognitive decline among cognitively normal individuals with elevated brain amyloid.
Exploratory analyses were conducted with longitudinal cognitive and biomarker data from 445 cognitively normal individuals in the United States and Canada. Participants were observed from August 23, 2005, to June 7, 2016, for a median of 3.1 years (interquartile range, 2.0-4.2 years; maximum follow-up, 10.3 years) as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI).
Individuals were classified at baseline as having normal (n = 243) or elevated (n = 202) brain amyloid using positron emission tomography amyloid imaging or a cerebrospinal fluid assay of amyloid β.
Outcomes included scores on the Preclinical Alzheimer Cognitive Composite (PACC; a sum of 4 baseline standardized z scores, which decreases with worse performance), Mini-Mental State Examination (MMSE; 0 worst to 30 best points), Clinical Dementia Rating Sum of Boxes (CDR-Sum of Boxes; 0 best to 18 worst points), and Logical Memory Delayed Recall (0 worst to 25 best story units).
Among the 445 participants (243 with normal amyloid, 202 with elevated amyloid), mean (SD) age was 74.0 (5.9) years, mean education was 16.4 (2.7) years, and 52% were women. The mean score for PACC at baseline was 0.00 (2.60); for MMSE, 29.0 (1.2); for CDR-Sum of Boxes, 0.04 (0.14); and for Logical Memory Delayed Recall, 13.1 (3.3). Compared with the group with normal amyloid, those with elevated amyloid had worse mean scores at 4 years on the PACC (mean difference, 1.51 points 95% CI, 0.94-2.10; P < .001), MMSE (mean difference, 0.56 points 95% CI, 0.32-0.80; P < .001), and CDR-Sum of Boxes (mean difference, 0.23 points 95% CI, 0.08-0.38; P = .002). For Logical Memory Delayed Recall, between-group score was not statistically significant at 4 years (mean difference, 0.73 story units 95% CI, -0.02 to 1.48; P = .056).
Exploratory analyses of a cognitively normal cohort followed up for a median of 3.1 years suggest that elevation in baseline brain amyloid level, compared with normal brain amyloid level, was associated with higher likelihood of cognitive decline, although the findings are of uncertain clinical significance. Further research is needed to assess the clinical importance of these differences and measure longer-term associations.
The Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study is an ongoing prevention trial in clinically normal older individuals with evidence of elevated brain amyloid. The large number ...of participants screened with amyloid positron emission tomography (PET) and standardized assessments provides an unprecedented opportunity to evaluate factors associated with elevated brain amyloid.
To investigate the association of elevated amyloid with demographic and lifestyle factors, apolipoprotein E (APOE), neuropsychological testing, and self- and study partner reports of cognitive function.
This cross-sectional study included screening data in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study collected from April 2014 to December 2017 and classified by amyloid status. Data were was analyzed from 2018 to 2019 across 67 sites in the US, Canada, Australia, and Japan and included 4486 older individuals (age 65-85 years) who were eligible for amyloid PET (clinically normal Clinical Dementia Rating = 0 and cognitively unimpaired Mini-Mental State Examination score, ≥25; logical memory IIa 6-18).
Screening demographics, lifestyle variables, APOE genotyping, and cognitive testing (Preclinical Alzheimer Cognitive Composite), self- and study partner reports of high-level daily cognitive function (Cognitive Function Index). Florbetapir amyloid PET imaging was used to classify participants as having elevated amyloid (Aβ+) or not having elevated amyloid (Aβ-).
Amyloid PET results were acquired for 4486 participants (mean SD age, 71.29 4.67 years; 2647 women 59%), with 1323 (29.5%) classified as Aβ+. Aβ+ participants were slightly older than Aβ-, with no observed differences in sex, education, marital or retirement status, or any self-reported lifestyle factors. Aβ+ participants were more likely to have a family history of dementia (3320 Aβ+ 74% vs 3050 Aβ- 68%) and at least 1 APOE ε4 allele (2602 Aβ+ 58% vs 1122 Aβ- 25%). Aβ+ participants demonstrated worse performance on screening Preclinical Alzheimer Cognitive Composite results and reported higher change scores on the Cognitive Function Index.
Among a large group of older individuals screening for an Alzheimer disease (AD) prevention trial, elevated brain amyloid was associated with family history and APOE ε4 allele but not with multiple other previously reported risk factors for AD. Elevated amyloid was associated with lower test performance results and increased reports of subtle recent declines in daily cognitive function. These results support the hypothesis that elevated amyloid represents an early stage in the Alzheimer continuum and demonstrate the feasibility of enrolling these high-risk participants in secondary prevention trials aimed at slowing cognitive decline during the preclinical stages of AD.
We conducted Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) and compared the basic characteristics and progression profiles with those of ADNI in North America.
A total of 537 Japanese ...subjects with normal cognition, late amnestic mild cognitive impairment (LMCI), or mild Alzheimer's disease (AD) were enrolled using the same criteria as ADNI. Rates of changes in representative cognitive or functional measures were compared for amyloid positron emission tomography- or cerebrospinal fluid amyloid β(1–42)-positive LMCI and mild AD between J-ADNI and ADNI.
Amyloid positivity rates were significantly higher in normal cognition of ADNI but at similar levels in LMCI and mild AD between J-ADNI and ADNI. Profiles of decline in cognitive or functional measures in amyloid-positive LMCI in J-ADNI (n = 75) and ADNI (n = 269) were remarkably similar, whereas those in mild AD were milder in J-ADNI (n = 73) compared with ADNI (n = 230).
These results support the feasibility of bridging of clinical trials in the prodromal stage of AD between Asia and western countries.
•Japanese Alzheimer's Disease Neuroimaging Initiative (ADNI) study was conducted using an almost identical protocol to ADNI.•The progression of amyloid-positive late mild cognitive impairment was quite similar between Japanese ADNI and ADNI.•The progression profiles of mild Alzheimer's disease were milder in Japanese ADNI compared with ADNI.•Bridging of Alzheimer's disease clinical trials between Asia and western countries will be supported.
Practitioners can be reassured that this antihistamine-releasing contact lens has no additional effect on corneal epithelial integrity.
To evaluate the effect of an antihistamine-releasing soft ...contact lens on corneal epithelium integrity when worn on a daily disposable modality for 12 weeks.
Two clinical trials using the same randomised, double-masked, placebo-controlled, parallel-group design enrolled healthy contact lens wearers. Participants wore either etafilcon A with 0.019 mg ketotifen (test; n = 374) or etafilcon A with no added drug (placebo; n = 186). Assessments were conducted at baseline, 1 week and 4, 8, and 12 weeks. Slit-lamp evaluations of corneal staining (using sodium fluorescein) in all regions of the corneas of both eyes were graded on a 0-4 scale. Data from all randomised participants were analysed.
Corneal staining was infrequent and, where present, was mild (Grade 2) or trace (Grade 1). There were no Grade 3 or 4 findings of corneal staining. The overall proportion of findings of Grade 0 corneal staining was 95.86% with the test lens and 95.88% with the placebo lens. The odds of no staining were not statistically different between the test and placebo lenses (Odds Ratio: 0.96, 95% Confidence Intervals: 0.76 to 1.20). There were no serious ocular adverse events or signs of ocular surface medicamentosa.
Both test and placebo lenses were well tolerated by subjects during the 3 months of wear. The antihistamine-releasing contact lens does not significantly impact corneal epithelial integrity.
Insulin modulates aspects of brain function relevant to Alzheimer disease and can be delivered to the brain using intranasal devices. To date, the use of intranasal insulin to treat persons with mild ...cognitive impairment and Alzheimer's disease dementia remains to be examined in a multi-site trial.
To examine the feasibility, safety, and efficacy of intranasal insulin for the treatment of persons with mild cognitive impairment and Alzheimer disease dementia in a phase 2/3 multisite clinical trial.
A randomized (1:1) double-blind clinical trial was conducted between 2014 and 2018. Participants received 40 IU of insulin or placebo for 12 months during the blinded phase, which was followed by a 6-month open-label extension phase. The clinical trial was conducted at 27 sites of the Alzheimer's Therapeutic Research Institute. A total of 432 adults were screened, and 144 adults were excluded. Inclusion criteria included adults aged 55 to 85 years with a diagnosis of amnestic mild cognitive impairment or Alzheimer disease (based on National Institute on Aging-Alzheimer Association criteria), a score of 20 or higher on the Mini-Mental State Examination, a clinical dementia rating of 0.5 or 1.0, and a delayed logical memory score within a specified range. A total of 289 participants were randomized. Among the first 49 participants, the first device (device 1) used to administer intranasal insulin treatment had inconsistent reliability. A new device (device 2) was used for the remaining 240 participants, who were designated the primary intention-to-treat population. Data were analyzed from August 2018 to March 2019.
Participants received 40 IU of insulin (Humulin-RU-100; Lilly) or placebo (diluent) daily for 12 months (blinded phase) followed by a 6-month open-label extension phase. Insulin was administered with 2 intranasal delivery devices.
The primary outcome (mean score change on the Alzheimer Disease Assessment Scale-cognitive subscale 12) was evaluated at 3-month intervals. Secondary clinical outcomes were assessed at 6-month intervals. Cerebrospinal fluid collection and magnetic resonance imaging scans occurred at baseline and 12 months.
A total of 289 participants (155 men 54.6%; mean SD age, 70.9 7.1 years) were randomized. Of those, 260 participants completed the blinded phase, and 240 participants completed the open-label extension phase. For the first 49 participants, the first device used to administer treatment had inconsistent reliability. A second device was used for the remaining 240 participants (123 men 51.3%; mean SD age, 70.8 7.1 years), who were designated the primary intention-to-treat population. No differences were observed between treatment arms for the primary outcome (mean score change on ADAS-cog-12 from baseline to month 12) in the device 2 ITT cohort (0.0258 points; 95% CI, -1.771 to 1.822 points; P = .98) or for the other clinical or cerebrospinal fluid outcomes in the primary (second device) intention-to-treat analysis. No clinically important adverse events were associated with treatment.
In this study, no cognitive or functional benefits were observed with intranasal insulin treatment over a 12-month period among the primary intention-to-treat cohort.
ClinicalTrials.gov Identifier: NCT01767909.
Pain is one of the most common reasons for seeking medical intervention, and self‐medication with over‐the‐counter medications and/or traditional herbal remedies has become increasingly popular. In ...this review, original articles on understanding possible herb–drug interactions between traditional herbs and four major pain medications—acetaminophen, aspirin, ibuprofen and naproxen—are compiled and analyzed. In terms of analytical methods, high‐performance liquid chromatography using an isocratic eluent system coupled to biological sample clean‐up is the most common, while a wide variety of detectors have been observed, including a photodiode array, variable wavelength detector, electrochemical detector and tandem mass spectrometer. Both synergistic and anti‐synergistic effects were observed for acetaminophen and aspirin, while only synergistic effects have been found for naproxen. Currently, no interactions have been reported for ibuprofen.
In this study, we fabricated gelatin/nano-hydroxyapatite/metformin scaffold (GHMS) and compared its effectiveness in bone regeneration with extraction-only, Sinbone, and Bio-Oss Collagen
groups in a ...critical size rat alveolar bone defect model. GHMS was synthesized by co-precipitating calcium hydroxide and orthophosphoric acid within gelatin solution, incorporating metformin, and cross-linked by microbial transglutaminase. The morphology, characterization, and biocompatibility of scaffold were examined. The in vitro effects of GHMS on osteogenic gene and protein expressions were evaluated. In vivo bone formation was assessed in a critical size rat alveolar bone defect model with micro-computed tomography and histological examination by comparing GHMS with extraction-only, Sinbone, and Bio-Oss Collagen
. The synthesized GHMS had a highly interconnected porous structure with a mean pore size of 81.85 ± 13.8 µm. GHMS exhibited good biocompatibility; promoted ALPL, RUNX2, SP7, BGLAP, SPARC and Col1a1 gene expressions; and upregulated the synthesis of osteogenic proteins, including osteonectin, osteocalcin, and collagen type I. In critical size rat alveolar bone defects, GHMS showed superior bone regeneration compared to extraction-only, Sinbone, and Bio-Oss Collagen
groups as manifested by greater alveolar ridge preservation, while more bone formation with a lower percentage of connective tissue and residual scaffold at the defect sites grafted with GHMS in histological staining. The GHMS presented in this study may be used as a potential bone substitute to regenerate alveolar bone. The good biocompatibility, relatively fast degradation, interconnected pores allowing vascularization, and higher bioactivity properties of the components of the GHMS (gelatin, nHA, and metformin) may contribute to direct osteogenesis.
Implant-related infection may be catastrophic and result in poor functional outcome, chronic osteomyelitis, implant failure or even sepsis and death. Based on a transglutaminase (TGase) ...cross-linked/antibiotics-encapsulated gelatin-alginate hydrogel, the main aim of this study is to establish an effective antibiotic slow-release system. The second aim is to evaluate the efficacy of a hydrogel-encapsulated antibiotic-containing titanium pin in preventing implant-related infections in a rat model. The prepared gelatin/alginate/gentamicin or vancomycin hydrogel was covalently cross-linked with transglutaminase (TGase). Its drug release profile and cytotoxicity were determined and the Wistar rat animal model was performed to validate its efficacy by radiographic examination, Micro-CT (computed tomography) evaluation and histo-morphological analysis at 12 weeks after surgery. When gelatin and alginate were thoroughly mixed with TGase, both 0.5% and 1.0% TGase can effectively cross link the hydrogel; the release of antibiotic is slowed down with higher degree of TGase concentration (from 20 min to more than 120 h). In the animal study, antibiotic-impregnated hydrogel is effective in alleviating the implant-related infections. Relative to that of a positive control group, the experimental group (vancomycin treatment group) showed significant higher bone volume, more intact bony structure with only mild inflammatory cell infiltration. This newly designed hydrogel can effectively deliver antibiotics to reduce bacterial colonization and biofilm formation on the implant surface. The remaining challenges will be to confer different potent antibacterial medications with good biocompatibility and fulfill the safety, practical and economic criteria for future clinical translation.
To evaluate the comfort performance of ACUVUE OASYS® 1-Day with HydraLuxe™ Technology among symptomatic contact lens wearers by using Contact Lens User Experience (CLUE) comfort scores and Contact ...Lens Dry Eye Questionnaire 8 (CLDEQ-8) discomfort and dryness scores.
Three clinical trials evaluated comfort and dryness when refitting symptomatic contact lens wearers to ACUVUE OASYS® 1-Day with HydraLuxe™ lenses. This analysis combined the CLUE comfort and CLDEQ-8 scores obtained at baseline and 2-week follow-up and compared average scores between visits. Subjects were grouped by habitual lens modality (daily disposable or daily wear reusable) and habitual lens material (silicone hydrogel or hydrogel). The analysis included data from 107 subjects.
Significant increases in mean CLUE comfort scores between baseline and 2-week follow-up occurred in all subject groups across habitual lens modality and material, indicating an improvement in overall comfort. CLUE comfort score improved clinically (≥5-point increase) among 75.7% of subjects (81/107). Similarly, significant decrease in mean CLDEQ-8 scores between baseline and 2-week follow-up occurred in all subject groups, indicating a decrease in the prevalence of dryness and discomfort symptoms. CLDEQ-8 score improved clinically (≥3-point reduction) among 82.2% of subjects (88/107). A majority of subjects (57.0%) became asymptomatic (CLDEQ-8 score ≤ 11 points) after 2 weeks of bilateral wear.
Refitting symptomatic contact lens patients to ACUVUE OASYS® 1-Day with HydraLuxe™ can improve overall comfort and reduce symptoms of dryness and discomfort, irrespective of the previous lens modality or habitual lens material.
PDF
