Combining plasma Aß and p-tau217 improves detection of brain amyloid in non-demented elderly.

BACKGROUND: Maximizing the efficiency to screen amyloid-positive individuals in asymptomatic and non-demented aged population using blood-based biomarkers is essential for future success of clinical trials in the early stage of Alzheimer's disease (AD). In this study, we elucidate the utility of combination of plasma amyloid-ß (Aß)-related biomarkers and tau phosphorylated at threonine 217 (p-tau217) to predict abnormal Aß-positron emission tomography (PET) in the preclinical and prodromal AD. METHODS: We designed the cross-sectional study including two ethnically distinct cohorts, the Japanese trial-ready cohort for preclinica and prodromal AD (J-TRC) and the Swedish BioFINDER study. J-TRC included 474 non-demented individuals (CDR 0: 331, CDR 0.5: 143). Participants underwent plasma Aß and p-tau217 assessments, and Aß-PET imaging. Findings in J-TRC were replicated in the BioFINDER cohort including 177 participants (cognitively unimpaired: 114, mild cognitive impairment: 63). In both cohorts, plasma Aß(1-42) (Aß42) and Aß(1-40) (Aß40) were measured using immunoprecipitation-MALDI TOF mass spectrometry (Shimadzu), and p-tau217 was measured with an immunoassay on the Meso Scale Discovery platform (Eli Lilly). RESULTS: Aß-PET was abnormal in 81 participants from J-TRC and 71 participants from BioFINDER. Plasma Aß42/Aß40 ratio and p-tau217 individually showed moderate to high accuracies when detecting abnormal Aß-PET scans, which were improved by combining plasma biomarkers and by including age, sex and APOE genotype in the models. In J-TRC, the highest AUCs were observed for the models combining p-tau217/Aß42 ratio, APOE, age, sex in the whole cohort (AUC = 0.936), combining p-tau217, Aß42/Aß40 ratio, APOE, age, sex in the CDR 0 group (AUC = 0.948), and combining p-tau217/Aß42 ratio, APOE, age, sex in the CDR 0.5 group (AUC = 0.955), respectively. Each subgroup results were replicated in BioFINDER, where the highest AUCs were seen for models combining p-tau217, Aß42/40 ratio, APOE, age, sex in cognitively unimpaired (AUC = 0.938), and p-tau217/Aß42 ratio, APOE, age, sex in mild cognitive impairment (AUC = 0.914). CONCLUSIONS: Combination of plasma Aß-related biomarkers and p-tau217 exhibits high performance when predicting Aß-PET positivity. Adding basic clinical information (i.e., age, sex, APOE Îµ genotype) improved the prediction in preclinical AD, but not in prodromal AD. Combination of Aß-related biomarkers and p-tau217 could be highly useful for pre-screening of participants in clinical trials of preclinical and prodromal AD.

Uptake and Use of Care Companion, a Web-Based Information Resource for Supporting Informal Carers of Older People: Mixed Methods Study.

BACKGROUND: Informal carers play a major role in supporting relatives and friends who are sick, disabled, or frail. Access to information, guidance, and support that are relevant to the lives and circumstances of carers is critical to carers feeling supported in their role. When unmet, this need is known to adversely affect carer resilience and well-being. To address this problem, Care Companion was co-designed with current and former carers and stakeholders as a free-to-use, web-based resource to provide access to a broad range of tailored information, including links to local and national resources. OBJECTIVE: This study aimed to investigate the real-world uptake and use of Care Companion in 1 region of England (with known carer population of approximately 100,000), with local health, community, and social care teams being asked to actively promote its use. METHODS: The study had a convergent parallel, mixed methods design and drew on the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework. Data included metrics from carers' use of Care Companion, surveys completed by users recruited through general practice, and interviews with carers and health and social care providers regarding their views about Care Companion and their response to it. Quantitative data were analyzed using descriptive statistics. Interview data were analyzed thematically and synthesized to create overarching themes. The qualitative findings were used for in-depth exploration and interpretation of quantitative results. RESULTS: Despite awareness-raising activities by relevant health, social care, and community organizations, there was limited uptake with only 556 carers (0.87% of the known carer population of 100,000) registering to use Care Companion in total, with median of 2 (mean 7.2; mode 2) visits per registered user. Interviews with carers (n=29) and stakeholders (n=12) identified 7 key themes that influenced registration, use, and perceived value: stakeholders' signposting of carers to Care Companion, expectations about Care Companion, activity levels and conflicting priorities, experience of using Care Companion, relevance to personal circumstances, social isolation and networks, and experience with digital technology. Although many interviewed carers felt that it was potentially useful, few considered it as being of direct relevance to their own circumstances. For some, concerns about social isolation and lack of hands-on support were more pressing issues than the need for information. CONCLUSIONS: The gap between the enthusiastic views expressed by carers during Care Companion's co-design and the subsequent low level of uptake and user experience observed in this evaluation suggests that the co-design process may have lacked a sufficiently diverse set of viewpoints. Numerous factors were identified as contributing to Care Companion's level of use, some of which might have been anticipated during its co-design. More emphasis on the development and implementation, including continuing co-design support after deployment, may have supported increased use.

Plasma and CSF biomarkers in a memory clinic: Head-to-head comparison of phosphorylated tau immunoassays.

INTRODUCTION: Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences. METHODS: In the BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non-AD cerebrospinal fluid (CSF) profile group, according to their amyloid beta 42/ phosphorylated tau (Aß42/p-tau) ratio. We performed a head-to-head comparison of nine plasma and nine CSF tau immunoassays and determined their accuracy to discriminate abnormal CSF Aß42/p-tau ratio. RESULTS: All studied plasma tau biomarkers were significantly higher in the AD CSF profile group compared to the non-AD CSF profile group and significantly discriminated abnormal CSF Aß42/p-tau ratio. For plasma p-tau biomarkers, the higher discrimination accuracy was shown by Janssen p-tau217 (r = 0.76; area under the curve [AUC] = 0.96), ADx p-tau181 (r = 0.73; AUC = 0.94), and Lilly p-tau217 (r = 0.73; AUC = 0.94). DISCUSSION: Several plasma p-tau biomarkers can be used in a specialized memory clinic as a stand-alone biomarker to detect biologically-defined AD. HIGHLIGHTS: Patients with an Alzheimer's disease cerebrospinal fluid (AD CSF) profile have higher plasma phosphorylated tau (p-tau) levels than the non-AD CSF profile group. All plasma p-tau biomarkers significantly discriminate patients with an AD CSF profile from the non-AD CSF profile group. Janssen p-tau217, ADx p-tau181, and Lilly p-tau217 in plasma show the highest accuracy to detect biologically defined AD. Janssen p-tau217, ADx p-tau181, Lilly p-tau217, Lilly p-tau181, and UGot p-tau231 in plasma show performances that are comparable to their CSF counterparts.

Plasma p-tau231 and p-tau217 as state markers of amyloid-ß pathology in preclinical Alzheimer's disease.

Blood biomarkers indicating elevated amyloid-ß (Aß) pathology in preclinical Alzheimer's disease are needed to facilitate the initial screening process of participants in disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient Aß pathology, but a comprehensive comparison with other putative blood biomarkers is lacking. In the ALFA+ cohort, all tested plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NfL and Aß42/40) were significantly changed in preclinical Alzheimer's disease. However, plasma p-tau231 reached abnormal levels with the lowest Aß burden. Plasma p-tau231 and p-tau217 had the strongest association with Aß positron emission tomography (PET) retention in early accumulating regions and associated with longitudinal increases in Aß PET uptake in individuals without overt Aß pathology at baseline. In summary, plasma p-tau231 and p-tau217 better capture the earliest cerebral Aß changes, before overt Aß plaque pathology is present, and are promising blood biomarkers to enrich a preclinical population for Alzheimer's disease clinical trials.

Instructional and Assessment Redesign of a Sterile Compounding Course Using Immersive Simulation.

Objective. To revise a traditional sterile compounding course to include content, competencies, and immersive simulations relevant to the current practice of sterile compounding pharmacy. Methods. Faculty and staff at the University of North Texas System College of Pharmacy made significant revisions to an existing sterile compounding course. Instruction was provided in didactic and laboratory sessions and delivered in three modules: fundamental skills, integration of skills and knowledge, and exceptions and specialty topics. Integration laboratory sessions consisted primarily of repetitive but increasingly difficult simulations that included both technician and pharmacist activities. Assessment methods included checkpoint assessments, a mock objective structured clinical examination (OSCE), a written examination, and a final comprehensive OSCE. Effectiveness of the course redesign was assessed by comparing student performance on assessments, overall course performance, and student perceptions extracted from the student course evaluation. Results. Of the 364 students enrolled in the sterile compounding course across four terms, 156 were in the pre-implementation cohort (cohort 1) and 208 were in the post-implementation cohort (cohort 2). Two hundred twenty-eight students completed the course evaluation. Course evaluations significantly demonstrated students' improved perceptions related to seven of 11 survey elements, most notably, critical thinking, integration of concepts, and students feeling challenged. Student performance on laboratory summative assessments also improved. However, written examination scores did not change. Conclusion. This novel sterile compounding course provided a practice-oriented blueprint for instruction and assessment of sterile compounding.

Improving Trauma Care in Africa.

Bringing the first Advanced Trauma Care for Nurses (ATCN) provider and instructor courses to Zimbabwe was the initial step in an educational partnership spanning more than 8,000 miles. Zimbabwe is a South African country with limited health care services, severe financial restraints, and a shortage of health care professionals. All of these barriers made our goal of bringing an organized and systematic approach to trauma care even more important. The nurses of Zimbabwe were aware that their patients were not receiving "best practice" care, which made them passionate for education, with strict enforcement of standardized delivery of care. The ATCN course provided the foundation for building a comprehensive approach to trauma care and creating a systematic and rapid initial assessment process during primary treatment of injured patients. Collaboration with the American College of Surgeons for the ATLS component was critical to the success and sustainability. The ultimate goal was to reduce morbidity and mortality from traumatic injuries and ultimately provide a sustained continuing education program to nurses countrywide. In November 2015, the Zimbabwe Nursing Council certified St. Philip's as its official National Nurse Trauma Training Center, the first and only center of its kind in Africa. As of October 2016, a total of 64 nurses have completed the ATCN courses and 9 have been checked off as ATCN faculty. Our goal was realized through the cooperation of many individuals. The nurses of Africa received the training crucial to delivering an excellent standard of care and ultimately saving lives.

The potent BACE1 inhibitor LY2886721 elicits robust central Aß pharmacodynamic responses in mice, dogs, and humans.

BACE1 is a key protease controlling the formation of amyloid ß, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid ß lowering in nonclinical animal models. Similar potent and persistent amyloid ß lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.

Up-regulation of astrocyte metabotropic glutamate receptor 5 by amyloid-ß peptide.

The effects of amyloid-beta peptide (Aß) on astrocyte responses to activation of mGlu5 receptors have been investigated using calcium imaging. Pre-incubation with Aß1-40 peptide for up to 72 h produced a time- and concentration-dependent 2-4 fold enhancement in the magnitude of the intracellular calcium mobilization response to the group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG). In contrast, pre-treatment with Aß1-40 did not alter the calcium responses induced by other G protein coupled- or ion channel-receptors. Aß 1-40-enhanced DHPG responses were blocked by the mGlu5 antagonist MPEP but not by inhibitors of voltage dependent calcium channels or by the AMPA/KA receptor antagonist CNQX. Up-regulation of mGlu5 coupled responses was associated with significant increases in astrocyte mGlu5 receptor-mRNA and-protein expression after preincubation with Aß . The changes observed in vitro were consistent with results obtained from human Alzheimer's disease (AD) patients.Immunostaining for mGlu5 receptors was increased on astrocytes which were colocalized with Aß plaques in hippocampal tissue from AD patients compared to age-matched controls. These results suggest that modulation of mGlu5 receptors in astrocytes could be an important mechanism in determining the progression of pathology in AD.

Development of homogeneous 384-well high-throughput screening assays for Abeta1-40 and Abeta1-42 using AlphaScreen technology.

Amyloid beta (Abeta) peptides are the major constituent of amyloid plaques, one of the hallmark pathologies of Alzheimer's disease. Accurate and precise quantitation of these peptides in biological fluids is a critical component of Alzheimer's disease research. The current most established assay for analysis of Abeta peptides in preclinical research is enzyme-linked immunosorbent assay (ELISA), which, although sensitive and of proven utility, is a multistep, labor-intensive assay that is difficult to automate completely. To overcome these limitations, the authors have developed and optimized simple, sensitive, homogeneous 384-well assays for Abeta1-42 and Abeta1-40 using AlphaScreen technology. The assays are capable of detecting Abeta peptides at concentrations <2 pg/mL and, using a final assay volume of 20 microL, routinely generate Z' values >0.85. The AlphaScreen format has the following key advantages: substantially less hands-on time to run, easier to automate, higher throughput, and less expensive to run than the traditional ELISA. The results presented here show that AlphaScreen technology permits robust, efficient, and cost-effective quantitation of Abeta peptides.