Alzheimer's disease therapeutic trials: EU/US Task Force report on recruitment, retention, and methodology.

While we may not be able to find a cure for Alzheimer's disease (AD) in the near future, several drugs presently in trials have shown promise as possible modifiers of disease progression. However, we may not be able to demonstrate efficacy due to issues of recruitment, retention, site-to-site variability, and other methodological issues. It is thus incumbent on the scientific community to find solutions to these problems, particularly as the field moves toward preventing illness or treating the disease in its prodromal stages, where these methodological issues will become even more critical. We need to better understand why participants agree or refuse to enter drug trials, and why both primary care physicians and Alzheimer's specialists agree or refuse to involve their patients. We also need to quantify the impact of requiring imaging studies, extensive questionnaires, cognitive testing, and lumbar punctures on recruitment and retention. With these concerns in mind, an international task force meeting of experts from academia and industry in the United States, European Union, and Japan in San Diego, California on November 2, 2011 to focus on recruitment, retention and other methodological issues related to clinical trials for AD. Based on the recommendations of this Task force meeting, this Perspectives article critically reflects on the most critical and timely methodological issues related to recruitment and retention in prevention and therapeutic trials in AD, which are paralleled by a paradigm shift in the diagnostic conceptualization of this disease, as reflected by recently new proposed diagnostic criteria involving preclinical stages of the disease.

A survey of attitudes about maternal serum screening for fetal chromosome abnormalities in women 35 years of age and older.

We asked two groups of women their opinion on prenatal diagnosis and maternal serum screening (MSS): group 1 comprised women who had undergone a prenatal diagnostic procedure (amniocentesis or chorionic villus sampling) for advanced maternal age (>/=35 years) and group 2 women who had undergone MSS and were 30-34 years old. Women in group 1 were found significantly less likely to choose MSS over prenatal diagnosis than were women in group 2. The sensitivity of MSS and the age-related risk of chromosome abnormalities influenced opinions on whether to choose MSS or prenatal diagnosis. In both groups, the majority stated that they would accept MSS over prenatal diagnosis, if their obstetrician recommended it.

Preparation of N epsilon B28-monoazidobenzoyl insulin-like growth factor I and photoaffinity labeling of insulin-like growth factor I receptor.

Recombinant human insulin-like growth factor I (hIGF-I) was reacted with azidobenzoyl hydroxysuccinimide to produce a mixture of photoactive hIGF-I derivatives. The mixture was purified by reversed-phase HPLC to yield three mono-substituted azidobenzoyl hIGF-Is. One of the derivatives was identified by amino acid sequencing as N epsilon B28-monoazidobenzoyl hIGF-I. This derivative was indistinguishable from native hIGF-I when bioassayed in Rat-1 fibroblasts. A 120-kDa band, the alpha subunit of the IGF-I receptor, was specifically labeled in Rat-1 plasma membranes by this photoprobe. The labeling of this band was reduced by hIGF-I at 1 nM and completely abolished by hIGF-I, but not insulin, at 100 nM, indicating the specificity of the photolabeling of the IGF-I receptor by this fully active IGF-I photoprobe.

Glucose transport in human skeletal muscle. The in vivo response to insulin.

Transmembrane glucose transport plays a key role in determining insulin sensitivity. We have measured in vivo WBGU, FGU, and K(in) and K(out) of 3-O-methyl-D-glucose in forearm skeletal muscle by combining the euglycemic clamp technique, the forearm-balance technique, and a novel dual-tracer (1-[3H]-L-glucose and 3-O-[14C]-methyl-D-glucose) technique for measuring in vivo transmembrane transport. Twenty-seven healthy, lean subjects were studied. During saline infusion, insulin concentration, FGU (n = 6), K(in), and K(out) (n = 4) were similar to baseline. During SRIF-induced hypoinsulinemia (insulin < 15 pM, n = 4) WBGU was close to 0, and FGU, K(in), and K(out) were unchanged from basal (insulin = 48 pM) values. During insulin clamps at plasma insulin levels of approximately 180 (n = 4), approximately 420 (n = 5), approximately 3000 (n = 4), and approximately 9500 pM (n = 4), WBGU was 14.2 +/- 1.3, 34.2 +/- 4.1 (P < 0.05 vs. previous step), 55.8 +/- 1.8 (P < 0.05 vs. previous step), and 56.1 +/- 6.3 mumol.min-1.kg-1 of body weight (NS vs. previous step), respectively. Graded hyperinsulinemia concomitantly increased FGU from a basal value of 4.7 +/- 0.5 mumol.min-1.kg-1 up to 10.9 +/- 2.3 (P < 0.05 vs. basal value), 26.6 +/- 4.5 (P < 0.05 vs. previous step), 54.8 +/- 4.3 (P < 0.05 vs. previous step), and 61.1 +/- 10.8 mumol.min-1.kg-1 of forearm tissues (NS vs. previous step), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Patterns of mood states in pregnant women undergoing chorionic villus sampling or amniocentesis.

The purpose of this study was to compare patterns of self-reported mood states of women having chorionic villus sampling (CVS) (n = 151) to those of women electing amniocentesis (n = 30) with the indication of advanced maternal age. Mood states were defined as scores on the 6 subscales of the Profile of Mood States (POMS). Women at 4 U.S. prenatal diagnostic facilities completed the POMS at 4 assessment periods. These were a) at their initial genetic counseling session, b) 2 weeks post CVS results (or an equivalent time), c) 2 weeks post amniocentesis results (or an equivalent time), and d) at 30 weeks gestation. Repeated measures analysis of variance revealed that anxiety, fatigue, and confusion decreased, and vigor increased in both groups as the pregnancy progressed. Depression decreased in both groups and then increased at assessment 4 in women in the amniocentesis group but not in those electing CVS. Results should be interpreted in conjunction with obstetrically and genetically-oriented findings regarding safety and accuracy to help women decide between the 2 procedures.

Resorbed co-twin as an explanation for discrepant chorionic villus results: non-mosaic 47,XX,+16 in villi (direct and culture) with normal (46,XX) amniotic fluid and neonatal blood.

Non-mosaic trisomy 16 was observed in chorionic villus cytotrophoblasts (direct) as well as cultured mesenchymal core cells derived from the pregnancy of a 38-year-old woman. Chromosome preparations from amniotic fluid and neonatal cultures (cord blood) were 46,XX. Normal fetal growth as determined by serial ultrasound examinations occurred throughout the pregnancy, which resulted in a healthy 2724 g female. Multiple biopsies taken from the umbilical cord, placental cotyledons, and fetal membranes were 46,XX. However, a placental nodule and three of six cultures initiated from membranes (amnion and chorion) showed 46,XX/47,XX,+16 mosaicism. We propose that the trisomy 16 cells arose from residual villi derived from a trisomic co-twin that never developed. This case further demonstrates that normal fetal growth may presage normal outcome irrespective of cytogenetic findings in cytotrophoblasts (direct) and cultured mesenchymal core cells.

Transabdominal chorionic villus sampling for first-trimester prenatal diagnosis.

We report here our technique and initial experience with transabdominal chorionic villus sampling for first-trimester prenatal diagnosis at the University of Tennessee, Memphis. Eighty-seven patients underwent transabdominal chorionic villus sampling between 9 and 12 menstrual weeks of pregnancy. Sufficient chorionic villi (greater than or equal to 5 mg) were obtained from 83 of the 87 patients (95.4%); in 73 (88%) of the 83 successful samplings only a single needle passage was required. In one case a 47,XX, +21 complement was diagnosed; the patient elected to terminate the pregnancy and the diagnosis was confirmed in the abortus. In a second case a 46,XX,rcp(15;21)(p11;q21) woman had a fetus who also had the same balanced translocation. In a third case nonmosaic 47,XX, +16 was detected in both direct preparations of cytotrophoblast cells and cultured mesenchymal core cells. Amniocentesis performed at 15 weeks showed a normal 46,XX complement. The pregnancy continued, and the patient was delivered at term of a healthy female infant. Two spontaneous fetal losses occurred in this series, and one woman underwent an elective abortion after receiving the results of a 46,XX complement. To date, 39 of the women have been delivered and all infants are doing well; the remaining 44 pregnancies are continuing uneventfully. We conclude that transabdominal chorionic villus sampling can be a useful alternative to transcervical chorionic villus sampling, particularly when transcervical sampling is contraindicated (e.g., active genital herpes) or where the transcervical approach would be technically difficult.