Ethical Issues in the Development of Readiness Cohorts in Alzheimer's Disease Research.

There is growing interest in the development of novel approaches to secondary prevention trials in Alzheimer's disease to facilitate screening and recruitment of research participants and to reduce the time and costs associated with clinical trials. Several international research collaborations are setting up research infrastructures that link existing research cohorts, studies or patient registries to establish 'trial-ready' or 'readiness' cohorts. From these cohorts, individuals are recruited into clinical trial platforms. In setting up such research infrastructures, researchers must make ethically challenging design decisions in at least three areas: re-contacting participants in existing research studies, obtaining informed consent for participation in a readiness cohort, and disclosure of Alzheimer's disease-related biomarkers. These ethical considerations have been examined by a dedicated workgroup within the European Prevention of Alzheimer's Dementia (EPAD) project, a trans-European longitudinal cohort and adaptive proof-of-concept clinical trial platform. This paper offers recommendations for the ethical management of re-contact, informed consent and risk disclosure which may be of value to other research collaborations in the process of developing readiness cohorts for prevention trials in Alzheimer's disease and other disease areas.

Psychological, behavioral and social effects of disclosing Alzheimer's disease biomarkers to research participants: a systematic review.

BACKGROUND: Current Alzheimer's disease (AD) research initiatives focus on cognitively healthy individuals with biomarkers that are associated with the development of AD. It is unclear whether biomarker results should be returned to research participants and what the psychological, behavioral and social effects of disclosure are. This systematic review therefore examines the psychological, behavioral and social effects of disclosing genetic and nongenetic AD-related biomarkers to cognitively healthy research participants. METHODS: We performed a systematic literature search in eight scientific databases. Three independent reviewers screened the identified records and selected relevant articles. Results extracted from the included articles were aggregated and presented per effect group. RESULTS: Fourteen studies met the inclusion criteria and were included in the data synthesis. None of the identified studies examined the effects of disclosing nongenetic biomarkers. All studies but one concerned the disclosure of APOE genotype and were conducted in the USA. Study populations consisted largely of cognitively healthy first-degree relatives of AD patients. In this group, disclosure of an increased risk was not associated with anxiety, depression or changes in perceived risk in relation to family history. Disclosure of an increased risk did lead to an increase in specific test-related distress levels, health-related behavior changes and long-term care insurance uptake and possibly diminished memory functioning. CONCLUSION: In cognitively healthy research participants with a first-degree relative with AD, disclosure of APOE ε4-positivity does not lead to elevated anxiety and depression levels, but does increase test-related distress and results in behavior changes concerning insurance and health. We did not find studies reporting the effects of disclosing nongenetic biomarkers and only one study included people without a family history of AD. Empirical studies on the effects of disclosing nongenetic biomarkers and of disclosure to persons without a family history of AD are urgently needed. TRIAL REGISTRATION: PROSPERO international prospective register for systematic reviews CRD42016035388 . Registered 19 February 2016.

Restoration of neuromuscular specificity following ventral rhizotomy in the bullfrog tadpole, Rana catesbeiana.

The specificity of hindlimb reinnervation following transection of lumbar ventral roots was investigated in adult and larval bullfrogs (Rana catesbeiana). Five to 6 weeks following ventral rhizotomy, the retrogradely transported marker horseradish peroxidase (HRP) was applied to circumscribed regions of the hindlimb. The location of labeled motoneuron somata within the lumbar lateral motor column was compared with that obtained in unoperated tadpoles. Reinnervation of the hindlimb was largely specific in tadpoles operated during the first third of larval life. However, localization was largely lost in older tadpoles and adult frogs. Repeated applications of 3H-thymidine combined with retrograde labeling with HRP failed to provide evidence that newly born motoneurons contribute to reinnervation of the hindlimb. Hindlimb reinnervation thus appears to result from regeneration of transected motor axons. In contrast to the lack of neuromuscular specificity seen in older animals after transection of ventral roots, motoneuron axons disconnected from their targets by crush injury regenerate to the appropriate limb regions.

Specificity of motoneuron projection patterns during development of the bullfrog tadpole (Rana catesbeiana).

The pattern of connectivity between motoneurons of the lumbar lateral motor column (LMC) and hindlimb regions was examined in bullfrog tadpoles (Rana catesbeiana) over the course of larval development. The purpose of this study was to determine if a period of relatively imprecise connectivity, such has been found in the toad Xenopus laevis (Lamb, '76), could be identified. Patterns of connectivity were assessed by placing small amounts of the retrogradely transported enzyme horseradish peroxidase (HRP) into discrete hindlimb regions and mapping the locations of labeled motoneuron somata along the transverse and longitudinal axes of the LMC. The distribution of labeled motoneurons was as circumscribed in the youngest animals studied (st. IV of Taylor and Kollros, '46), before mesenchymal condensation into distinct myotubes, as in metamorphic or adult animals. This finding that the pattern of neuromuscular connectivity is as precise early in development as in mature animals is consistent with previous studies of chick hindlimb (Landmesser, '78). The relevance of these results to the hypothesis that naturally occurring cell death plays a substantial part in molding the mature pattern of neuromuscular connectivity (Lamb, '77) is discussed.

Retrograde labeling of migrating spinal motoneurons in bullfrog larvae.

Horseradish peroxidase (HRP) was applied to the ventral root or developing limb bud of bullfrog tadpoles. In animals younger than Stage XII/XIII [9] ventral root application consistently labeled neurons located between the lateral motor column (LMC) and the neuroepithelium. Only occasional motoneurons outside the LMC were labeled in animals older than Stage XIV/XV. Limb bud application of HRP in any-stage tadpole did not label ectopic LMC motoneurons. These results indicate that LMC motoneurons have sent their axons out the ventral root before completion of migration but that these axons may not as yet have reached the limb bud.