Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial.

The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.

Improving CSF biomarker accuracy in predicting prevalent and incident Alzheimer disease.

OBJECTIVE: To investigate factors, including cognitive and brain reserve, which may independently predict prevalent and incident dementia of the Alzheimer type (DAT) and to determine whether inclusion of identified factors increases the predictive accuracy of the CSF biomarkers Aß(42), tau, ptau(181), tau/Aß(42), and ptau(181)/Aß(42). METHODS: Logistic regression identified variables that predicted prevalent DAT when considered together with each CSF biomarker in a cross-sectional sample of 201 participants with normal cognition and 46 with DAT. The area under the receiver operating characteristic curve (AUC) from the resulting model was compared with the AUC generated using the biomarker alone. In a second sample with normal cognition at baseline and longitudinal data available (n = 213), Cox proportional hazards models identified variables that predicted incident DAT together with each biomarker, and the models' concordance probability estimate (CPE), which was compared to the CPE generated using the biomarker alone. RESULTS: APOE genotype including an ε4 allele, male gender, and smaller normalized whole brain volumes (nWBV) were cross-sectionally associated with DAT when considered together with every biomarker. In the longitudinal sample (mean follow-up = 3.2 years), 14 participants (6.6%) developed DAT. Older age predicted a faster time to DAT in every model, and greater education predicted a slower time in 4 of 5 models. Inclusion of ancillary variables resulted in better cross-sectional prediction of DAT for all biomarkers (p < 0.0021), and better longitudinal prediction for 4 of 5 biomarkers (p < 0.0022). CONCLUSIONS: The predictive accuracy of CSF biomarkers is improved by including age, education, and nWBV in analyses.

Alzheimer disease identification using amyloid imaging and reserve variables: proof of concept.

OBJECTIVE: Several factors may influence the relationship between Alzheimer disease (AD) lesions and the expression of dementia, including those related to brain and cognitive reserve. Other factors may confound the association between AD pathology and dementia. We tested whether factors thought to influence the association of AD pathology and dementia help to accurately identify dementia of the Alzheimer type (DAT) when considered together with amyloid imaging. METHODS: Participants with normal cognition (n = 180) and with DAT (n = 25), aged 50 years or older, took part in clinical, neurologic, and psychometric assessments. PET with the Pittsburgh compound B (PiB) tracer was used to measure brain amyloid, yielding a mean cortical binding potential (MCBP) reflecting PiB uptake. Logistic regression was used to generate receiver operating characteristic curves, and the areas under those curves (AUC), to compare the predictive accuracy of using MCBP alone vs MCBP together with other variables selected using a stepwise selection procedure to identify participants with DAT vs normal cognition. RESULTS: The AUC resulting from MCBP alone was 0.84 (95% confidence interval [CI] = 0.73-0.94; cross-validated AUC = 0.80, 95% CI = 0.68-0.92). The AUC for the predictive equation generated by a stepwise model including education, normalized whole brain volume, physical health rating, gender, and use of medications that may interfere with cognition was 0.94 (95% CI = 0.90-0.98; cross-validated AUC = 0.91, 95% CI = 0.85-0.96), an improvement (p = 0.025) over that yielded using MCBP alone. CONCLUSION: Results suggest that factors reported to influence associations between AD pathology and dementia can improve the predictive accuracy of amyloid imaging for the identification of symptomatic AD.

Radiologists' perception of professional journals.

RATIONALE AND OBJECTIVES: We assessed radiologists' perceptions of radiologic and general medical journals. METHODS: Five thousand randomly chosen radiologists (4,200 American College of Radiology (ACR) members and 800 members in training) were surveyed by mail concerning their opinion of selected radiology and major medical journals. The mail survey was followed up by a phone survey of 45 previously unsurveyed radiologists from a smaller list of a similar ACR population. RESULTS AND CONCLUSIONS: Of the 5,000 surveys mailed out, 987 (20%) were completed and returned. There were no systematic differences in the questionnaire results between those surveyed by phone and those surveyed by mail. In general, academic radiologists, private practice radiologists, and radiologists in training did not differ in their assessment of professional journals. The respondents picked Radiology as their first choice if they were allowed to read only one journal. The respondents believed that Radiology published the best clinical research and Investigative Radiology the best basic science research. American Journal of Roentgenology (AJR), Radiology, and Journal of Computer Assisted Tomography ranked highest for sureness and rapidity of manuscript acceptance and publication, while Radiology, New England Journal of Medicine, and the Journal of the American Medical Association ranked highest in terms of exposure and prestige.

Effects of calcium on the dynamic process of transmitter release which generates either skew- or bell-MEPPS.

Miniature endplate potential (MEPP) amplitudes, MEPP frequencies and ratios of skew:bell-MEPPs were determined as well as synaptic vesicle diameters and densities at the mouse diaphragm neuromuscular endplate during exposure to elevated calcium concentrations. Additions of external Ca2+ had variable effects on MEPP frequencies and percentages of skew-MEPPs, regardless of concentrations used (1-25 mM). Nevertheless, changes in MEPP amplitudes were most sensitive (4-fold decrease) to low value increases of Ca2+. Changes in MEPP frequencies produced by an increase in Ca2+ were very sensitive to initial frequencies as well as the initial calcium concentration. An increase in Ca2+ usually increased MEPP frequency (providing skew-MEPPs were measured). Changes in the percentage of skew-MEPPs were extremely variable (4-90%) and these changes depended on initial frequencies, initial skew- to bell-MEPP ratios and age of the mouse. With a change in Ca2+ concentration, synaptic vesicle diameters and densities remained constant during changes in MEPP frequencies and large changes in the skew:bell-MEPP ratios; and, vesicle numbers were sometimes slightly increased. Because of the wide range in MEPP frequencies and amplitudes, this study demonstrates that the effect of various treatments should be evaluated on identified endplates and that analyses of randomly selected endplates must consider the large variability between endplates. These results show that the skew-MEPP class must not be ignored in studies of spontaneous MEPP release, and that initial frequencies and age of the mouse are also important in evaluating changes in skew-MEPP to bell-MEPP ratios. The rapid changes in skew- to bell-MEPP classes indicate that MEPP class and size are determined at the moment of release by the state of the release process as proposed by Kriebel et al. (1990). Because changes in calcium concentration can immediately alter the ratio of skew- to bell-MEPPs we conclude that the release process has two states to generate the two classes of MEPPs, and that the release process is very sensitive to conditions so that states are easily changed. We propose that the release process meters transmitter in subunit amounts to form both classes of MEPPS and that the calcium ions modulate the process.

Achilles tendon injuries: the role of MR imaging.

Eight magnetic resonance (MR) examinations were performed in seven patients with Achilles tendon injuries and correlated with physical examination and surgical and clinical follow-up. The MR examinations depicted the Achilles tendon in excellent detail and Achilles tendon abnormalities with greater accuracy than physical examination. Of five tendons shown to be at least partially torn on MR, palpable tendinous defects were found in only one, and plantarflexion weakness was found in four. The MR and surgical findings precisely correlated in one case. Magnetic resonance proved valuable in the evaluation of clinically equivocal Achilles tendon tears and may ultimately play a greater role as a research tool in the determination of optimal forms of therapy for specific Achilles tendon injuries.

New technique of injection of estradiol into preoptic-anterior hypothalamic area of newborn rats: technique limiting diffusion and duration, with preliminary results on postpuberal block of ovulation.

Previous studies have shown that sc administration of androgen or estrogen into newborn female rats will disturb postpuberal ovulatory function, as evidenced by a higher incidence of vaginal estrus, few ovarian corpora lutea, and the abolition of estrogen-induced luteinizing hormone surges after ovariectomy and chronic estrogen maintenance. Studies of the uptake of labeled estrogen and intracerebral lesion studies have indicated the preoptic area and anterior hypothalamic nuclei (POA-AH) as possible sites of steroid uptake and control of certain sexual functions in the rat. Attempts to localize the site of steroid effects to the POA-AH of newborn rats by chronic implants have been hampered by lack of definition of extent of localization in space and time. The present study introduces a microinjection technique for the delivery of subpicogram quantities of estradiol to these areas of the central nervous system in newborn rats, and statistically defines the extent of steroid localization in three dimensions as well as the duration of exposure. Delivery of estradiol by this method in the POA-AH region yielded an increased incidence of postpuberal vaginal estrus; a decrease in the number of corpora lutea; and in many but not all, led to abolition of estrogen-progesterone induced LH surges after castration and estrogen replacement. Injection 0.5 mm more caudad did not result in blockade of the estrous cycle.