Prediction of Cognitive Decline for Enrichment of Alzheimer's Disease Clinical Trials.

BACKGROUND: A key issue to Alzheimer's disease clinical trial failures is poor participant selection. Participants have heterogeneous cognitive trajectories and many do not decline during trials, which reduces a study's power to detect treatment effects. Trials need enrichment strategies to enroll individuals who are more likely to decline. OBJECTIVES: To develop machine learning models to predict cognitive trajectories in participants with early Alzheimer's disease and presymptomatic individuals over 24 and 48 months respectively. DESIGN: Prognostic machine learning models were trained from a combination of demographics, cognitive tests, APOE genotype, and brain imaging data. SETTING: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), National Alzheimer's Coordinating Center (NACC), Open Access Series of Imaging Studies (OASIS-3), PharmaCog, and a Phase 3 clinical trial in early Alzheimer's disease were used for this study. PARTICIPANTS: A total of 2098 participants who had demographics, cognitive tests, APOE genotype, and brain imaging data, as well as follow-up visits for 24-48 months were included. MEASUREMENTS: Baseline magnetic resonance imaging, cognitive tests, demographics, and APOE genotype were used to separate decliners, defined as individuals whose CDR-Sum of Boxes scores increased during a predefined time window, from stable individuals. A prognostic model to predict decline at 24 months in early Alzheimer's disease was trained on 1151 individuals who had baseline diagnoses of mild cognitive impairment and Alzheimer's dementia from ADNI and NACC. This model was validated on 115 individuals from a placebo arm of a Phase 3 clinical trial and 76 individuals from the PharmaCog dataset. A second prognostic model to predict decline at 48 months in presymptomatic populations was trained on 628 individuals from ADNI and NACC who were cognitively unimpaired at baseline. This model was validated on 128 individuals from OASIS-3. RESULTS: The models achieved up to 79% area under the curve (cross-validated and out-of-sample). Power analyses showed that using prognostic models to recruit enriched cohorts of predicted decliners can reduce clinical trial sample sizes by as much as 51% while maintaining the same detection power. CONCLUSIONS: Prognostic tools for predicting cognitive decline and enriching clinical trials with participants at the highest risk of decline can improve trial quality, derisk endpoint failures, and accelerate therapeutic development in Alzheimer's disease.

Rostral-Caudal Hippocampal Functional Convergence Is Reduced Across the Alzheimer's Disease Spectrum.

Beginning in the early stages of Alzheimer's disease (AD), the hippocampus reduces its functional connections to other cortical regions due to synaptic depletion. However, little is known regarding connectivity abnormalities within the hippocampus. Here, we describe rostral-caudal hippocampal convergence (rcHC), a metric of the overlap between the rostral and caudal hippocampal functional networks, across the clinical spectrum of AD. We predicted a decline in rostral-caudal hippocampal convergence in the early stages of the disease. Using fMRI, we generated resting-state hippocampal functional networks across 56 controls, 48 early MCI (EMCI), 35 late MCI (LMCI), and 31 AD patients from the Alzheimer's Disease Neuroimaging Initiative cohort. For each diagnostic group, we performed a conjunction analysis and compared the rostral and caudal hippocampal network changes using a mixed effects linear model to estimate the convergence and differences between these networks, respectively. The conjunction analysis showed a reduction of rostral-caudal hippocampal convergence strength from early MCI to AD, independent of hippocampal atrophy. Our results demonstrate a parallel between the functional convergence within the hippocampus and disease stage, which is independent of brain atrophy. These findings support the concept that network convergence might contribute as a biomarker for connectivity dysfunction in early stages of AD.

[Management and prevention of abuse in Quebec: a program of sociolegal pediatrics at the Sainte-Justine Hospital in Montreal]. / Prise en charge et prévention de la maltraitance au Québec: programme de pédiatrie sociojuridique de l'hôpital Sainte-Justine à Montréal.

In Quebec, the Child's Protection law protects the child from birth until 18 years of age when child abuse or neglect is suspected. Since 1990, the program of the Child Protection Clinic of Sainte-Justine Hospital (Montreal) offers a special unit for evaluation and prevention of child abuse and neglect, constituted by a multidisciplinary team including five pediatricians. About 500 children are referred each year in external consultations or from hospital units. In addition, the pediatricians participate in the "programme Santé-Enfance-Jeunesse", a prevention program in the Montreal area. They also act as expert witnesses in court. Thus Quebec's pediatricians fully participate in a child's protection with their activities in different levels of diagnosis, management and prevention of child abuse and neglect.

Pattern of child sexual abuse by young aggressors.

OBJECTIVE: The aim of the study was to determine whether sexual victimization of children by young aggressors differs from adult aggressors. METHOD: A case review was performed on medical records of children less than 12 years of age referred in 1992 to the Child Protection Clinic at a tertiary care pediatric hospital. RESULTS: Medical evaluation for sexual abuse was carried out on 316 children, 79% girls, 21% boys, mean age 6 +/- 2.7 years. Among known perpetrators, 39 were less than 16 years and 15 were between 16 and 19 years old. Young aggressors were more likely to abuse older female victims (p = .0009). They also were reported to engage in more genital/genital and genital/anal acts (p < .001). The aggressor's young age was found to be an important determinant related to a history of penetrative forms of sexual abuse (OR = 4.015, 95% C.I. 2.0581; 7.8319). Genital examination was specific for abuse (Adam's Class IV or V) in only 6.3% of victims, but significantly more often when the perpetrator was between 16-19 years old (p = .003). CONCLUSIONS: Adolescent aggressors appear to engage in more genital/genital and genital/anal sexual abuse than older aggressors. Victims of aggressors age 16 to 19 had a higher risk of having specific findings on the anal/genital examination.

Cariogenic feeding habits and fluoride supplementation during infancy and early childhood.

Parents of 240 children between nine months and three years of age were interviewed using a questionnaire in order to determine cariogenic feeding habits and fluoride supplementation. Mean age of weaning from the bottle was 14.6 months. After 18 months of age, children from minority ethnic groups were more frequently bottle-fed than French-Canadian children (p < .005). Giving a bottle in bed (34.6% of cases) was more often practised by less educated mothers (p = .007) or by minority ethnic groups (p = .002), and was seen as a cariogenic factor by 31% of parents. Fluoride was given in half of cases, mainly by highly educated mothers (p = .001) and was mentioned as a preventive measure by 27% of parents. Physicians should be aware of poor parental knowledge and practices of preventive dentistry, and must discuss cariogenic feeding habits and fluoride supplementation during well-baby visits.

[Parental knowledge about their asthmatic children]. / Connaissances des parents d'enfants asthmatiques.

A questionnaire was administered to parents of 171 asthmatic children, and their knowledge of asthma was evaluated using a quantitative score. The mean age of children was 5 yr and the mean duration of their asthma was 3 yr. Each sign of the classical triad "noisy breathing, cough, indrawing" was mentioned by two-thirds of parents. Inhaled agents perceived as triggers of asthma were: animal hair (73.7%), dust (69.6%), pollen (60.2%), tobacco (44.4%), molds (14.6%). Other triggering agents mentioned were: stress (51.5%), infections (38%), exercise (13.5%). Mothers with college or university education knew more clinical signs of an attack (P less than 0.01) and more triggering factors (P less than 0.005). Parents satisfied with previous teaching knew more threatening signs of an attack (P less than 0.01). About 80% of those that used theophylline and 49.4% of those that used inhaled beta-2-agonists knew the correct mode of administration. Parents satisfied with previous teaching had better knowledge of the side-effects of theophylline (P less than 0.005) and beta-2-agonists (P less than 0.02). 58.5% of those that used cromolyn sodium did not know the mean duration of a therapeutic trial and 15% did not use it as prophylaxis. 57.1% of those that used oral corticosteroids did not know any side-effects of the drug. About half of the parents indicated that they would like to receive more information about the causes and the appropriate treatment of asthma. It was concluded that parental teaching should focus more on environmental and therapeutic issues.