Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 µg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

The source of cognitive complaints predicts diagnostic conversion differentially among nondemented older adults.

OBJECTIVE: The objective of this study was to compare whether different sources of cognitive complaint (i.e., subjective and informant) predict diagnostic conversion in nondemented older adults. METHODS: Participants from the National Alzheimer's Coordinating Center had a baseline diagnosis of normal cognition (NC; n = 4414; mean age, 73 ± 8 years; 69% female) or mild cognitive impairment (MCI; n = 1843; mean age, 74 ± 8 years; 52% female). Multinomial logistic regression related baseline cognitive complaint (no complaint, self only, informant only, or both self and informant) to diagnostic outcome (reversion, stable, or conversion). RESULTS: At follow-up, 14% of NC participants converted to MCI/dementia (3.5 ± 1.8 years), and 41% of MCI participants converted to dementia (3.0 ± 1.6 years). Among NC participants, self complaint only (odds ratio [OR], 2.1; 99% confidence interval (CI),1.5-2.9; P < .001), informant complaint only (OR, 2.2; 99% CI, 1.2-3.9; P < .001), and both self and informant complaint (OR, 4.2; 99% CI, 2.9-6.0; P < .001) were associated with diagnostic conversion compared with no complaint. Among participants with MCI-compared with no complaint, informant complaint only (OR, 2.2; 99% CI, 1.2-4.3, P = .002), and both self and informant complaint (OR, 2.9; 99% CI, 1.8-4.8; P < .001)-were associated with conversion. CONCLUSIONS: Cognitive complaints are related to conversion among nondemented older adults. Complaint from both (i.e. mutual complaint) sources was most predictive of diagnostic outcome, followed by informant complaint, highlighting the need for obtaining informant corroboration to enhance prognosis and distinguish underlying pathological processes from normal cognitive aging. Self complaint was related inconsistently to diagnostic outcome.

Clinical research risk assessment among individuals with mild cognitive impairment.

OBJECTIVE: : To determine whether individuals with mild cognitive impairment (MCI) differ from cognitively normal (NC) elders on a risk assessment task and whether participants and their study partners evaluate risk and benefit similarly. DESIGN: : Cross-sectional. SETTING: : University medical setting. PARTICIPANTS: : Seventy-nine participants (NC, n = 40; MCI, n = 39), age 60-90 years (73 ± 7 years; 53% women), and 64 study partners (NC, n = 36; MCI, n = 28), age 38-84 years (68 ± 10 years; 67% women). MEASUREMENTS: : Participants and study partners completed a risk assessment task that involved ranking from least to most risk four hypothetical vignettes for memory loss research (brain autopsy, blood draw, oral medication, neurosurgery). Participants also completed decisional capacity for research and neuropsychological protocols. RESULTS: : MCI participants' risk rankings differed from NC risk rankings (p <0.001) with MCI participants ranking brain autopsy higher and an oral medication trial lower. Demographic, decisional capacity, and neuropsychological variables could not explain MCI participant performances. Participants and their study partners had comparable risk assessment performance (p = 1.0). MCI study partners performed similar to their MCI participant counterparts but were different from NC study partners (p = 0.002; i.e., ranking autopsy higher and oral medication lower). CONCLUSION: : Findings suggest that individuals with MCI assess risk differently than NC peers by overestimating the risk (or underestimating the benefit) of brain autopsy and underestimating the risk (or overestimating the benefit) of oral medication. Study partners display a similar pattern. These observations may be secondary to MCI participants' (and their study partners') personal connection to the potential benefits of an experimental medication for memory loss.

Medical student education program in Alzheimer's disease: the PAIRS Program.

BACKGROUND: As life expectancy increases, dementia incidence will also increase, creating a greater need for physicians well-trained to provide integrated geriatric care. However, research suggests medical students have limited knowledge or interest in pursuing geriatric or dementia care. The purpose of this study is to evaluate the PAIRS Program and its effectiveness in enhancing medical education as a service-learning activity and replication model for the Buddy ProgramTM. METHODS: Between 2007 and 2011, four consecutive classes of first year Boston University School of Medicine students (n = 45; 24 ± 3 years, 58% female, 53% White) participated in a year-long program in which they were paired with a patient with early-stage Alzheimer's disease (AD). Assessments included pre- and post-program dementia knowledge tests and a post-program reflective essay. RESULTS: Program completion was 100% (n = 45). A paired-sample t-test revealed a modest improvement in dementia knowledge post-program (p < 0.001). Using qualitative coding methods, 12 overarching themes emerged from the students' reflective essays, such as observing care partner burden, reporting a human side to AD, reporting experiences from the program that will impact future clinical practice, and obtaining a greater understanding of AD. CONCLUSIONS: Quantitative and qualitative findings suggest that the PAIRS Program can enhance the acquisition of knowledge, skills, and positive attitudes regarding geriatric healthcare in future generations of physicians, a skill set that is becoming increasingly relevant in light of the rapidly aging population. Furthermore, results suggest that The Buddy ProgramTM model can be successfully replicated.

Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome.

Objective: To measure the efficacy of mecasermin (recombinant human insulin-like growth factor 1, rhIGF-1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double-blind crossover study design. Methods: Thirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF-1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28-week washout period. The primary endpoints were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behaviour Questionnaire (RSBQ) Fear/Anxiety subscale, Parent Target Symptom Visual Analog Scale (PTSVAS) top three concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale. Cardiorespiratory- and electroencephalography (EEG)-based biomarkers were also analyzed. Results: There were no significant differences between randomization groups. The majority of AEs were mild to moderate, although 12 episodes of serious AEs occurred. The Kerr severity scale, ADAMS Depressed Mood subscale, Visual Analog Scale Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms. Electroencephalography (EEG) parameters also deteriorated. A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings. However, it also revealed improvements on a measure of stereotypic behavior and another of social communication. Interpretation: As in the phase 1 trial, rhIGF-1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.

Anxiety-like behavior in Rett syndrome: characteristics and assessment by anxiety scales.

BACKGROUND: Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by regression of language and motor skills, cognitive impairment, and frequent seizures. Although the diagnostic criteria focus on communication, motor impairments, and hand stereotypies, behavioral abnormalities are a prevalent and disabling component of the RTT phenotype. Among these problematic behaviors, anxiety is a prominent symptom. While the introduction of the Rett Syndrome Behavioral Questionnaire (RSBQ) represented a major advancement in the field, no systematic characterization of anxious behavior using the RSBQ or other standardized measures has been reported. METHODS: This study examined the profiles of anxious behavior in a sample of 74 girls with RTT, with a focus on identifying the instrument with the best psychometric properties in this population. The parent-rated RSBQ, Anxiety, Depression, and Mood Scale (ADAMS), and Aberrant Behavior Checklist-Community (ABC-C), two instruments previously employed in children with neurodevelopmental disorders, were analyzed in terms of score profiles, relationship with age and clinical severity, reliability, concurrent validity, and functional implications. The latter were determined by regression analyses with the Vineland Adaptive Behavior Scales-Second Edition (Vineland-II) and the Child Health Questionnaire (CHQ), a quality of life measure validated in RTT. RESULTS: We found that scores on anxiety subscales were intermediate in range with respect to other behavioral constructs measured by the RSBQ, ADAMS, and ABC-C. Age did not affect scores, and severity of general anxiety was inversely correlated with clinical severity. We demonstrated that the internal consistency of the anxiety-related subscales were among the highest. Test-retest and intra-rater reliability was superior for the ADAMS subscales. Convergent and discriminant validity were measured by inter-scale correlations, which showed the best profile for the social anxiety subscales. Of these, only the ADAMS Social Avoidance showed correlation with quality of life. CONCLUSIONS: We conclude that anxiety-like behavior is a prominent component of RTT's behavioral phenotype, which affects predominantly children with less severe neurologic impairment and has functional consequences. Based on available data on standardized instruments, the ADAMS and in particular its Social Avoidance subscale has the best psychometric properties and functional correlates that make it suitable for clinical and research applications.