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Measures of adaptive behavior are important in the assessment and treatment of individuals with intellectual disabilities (ID). The purpose of the current study was to evaluate the stability of an established and a novel measure of adaptive behavior over time, and their suitability as outcome measures in clinical trials targeting individuals with Down syndrome (DS). This 6-month, longitudinal, noninterventional, multinational study included adolescents (12-17 years) and adults (18-30 years) with DS. Participants were from seven countries (11 different sites) with English, Spanish and French as their native language. The Vineland Adaptive Behavior Scales-II (VABS-II) and a newly developed Clinician Global Impression (CGI) scale were administered at baseline, 1 and 6 months. Adults had lower composite standard scores on all domains of the VABS-II compared with adolescents. The communication domain was a weakness relative to the socialization and daily living skills domains on the VABS-II and the CGI-Severity scale. These findings were stable over 6 months, as exhibited by high intraclass correlations (>0.75). These results provide valuable baseline data for use in trial design and endpoint selection for studies including individuals with DS. ClinicalTrials.gov identifier: NCT01580384.

Following the completion of a 20-week, open-label study of the safety and efficacy of liquid rivastigmine for adolescents with Down syndrome, 5 of the 10 adolescents in the clinical trial continued long-term rivastigmine therapy and 5 did not. After an average period of 38 months, all 10 subjects returned for a follow-up assessment to determine the safety and efficacy of long-term rivastigmine use. Rivastigmine was well tolerated and overall health appeared to be unaffected by long-term rivastigmine use. Performance change on cognitive and language measures administered at the termination of the open-label clinical trial was compared between the two groups. No between-group difference in median performance change across the long-term period was found, suggesting that the long-term use of rivastigmine does not improve cognitive and language performance. However, two subjects demonstrated remarkable improvement in adaptive function over the long-term period. Both subjects had received long-term rivastigmine therapy. The discussion addresses the challenge of assessing cognitive change in clinical trials using adolescents with Down syndrome as subjects and the use of group versus individual data to evaluate the relevance of medication effects.

The objective of this 10-week, randomized, double-blind, placebo-controlled multicenter study was to assess the efficacy and safety of donepezil for the treatment of cognitive dysfunction exhibited by children with Down syndrome (DS). Intervention comprised donepezil (2.5–10 mg/day) in children (aged 10–17 years) with DS of mild-to-moderate severity. The primary measures were the Vineland-II Adaptive Behavior Scales (VABS-II) Parent/Caregiver Rating Form (PCRF) the sum of nine subdomain standardized scores and standard safety measures. Secondary measures included the VABS-II/PCRF scores on the following domains and their respective individual subdomains: Communication (receptive, expressive, and written); Daily Living Skills (personal, domestic, and community); Socialization (interpersonal relationships, play and leisure time, and coping skills), and scores on the Test of Verbal Expression and Reasoning, a subject-performance-based measure of expressive language. At baseline, 129 participants were assigned treatment with donepezil or placebo. During the double-blind phase, VABS II/PCRF sum of the nine subdomain standardized scores, called v-scores, improved significantly from baseline in both groups (P

Deficiency of acid alpha glucosidase (GAA) causes Pompe disease, which is usually fatal if onset occurs in infancy. Patients synthesize a non-functional form of GAA or are unable to form native enzyme. Enzyme replacement therapy with recombinant human GAA (rhGAA) prolongs survival in infantile Pompe patients but may be less effective in cross-reactive immunologic material (CRIM)-negative patients. We retrospectively analyzed the influence of CRIM status on outcome in 21 CRIM-positive and 11 CRIM-negative infantile Pompe patients receiving rhGAA. Patients were from the clinical setting and from clinical trials of rhGAA, were 6 months of age, were not invasively ventilated, and were treated with IV rhGAA at a cumulative or total dose of 20 or 40 mg/kg/2 weeks. Outcome measures included survival, invasive ventilator-free survival, cardiac status, gross motor development, development of antibodies to rhGAA, and levels of urinary Glc(4). Following 52 weeks of treatment, 6/11 (54.5%) CRIM-negative and 1/21 (4.8%) CRIM-positive patients were deceased or invasively ventilated (p

There is growing evidence to support the use of early central cholinergic enhancement to improve cognitive functioning in individuals with Down syndrome (DS). This report summarizes preliminary safety and cognitive efficacy data for seven children (8-13 years) with DS who participated in a 22-week, open-label trial of donepezil hydrochloride. Donepezil was dosed once daily at 2.5 mg and, based on tolerability, increased to 5 mg/day. Safety assessments were conducted at Week 1 (baseline), Week 8 (2.5 mg donepezil), Week 16 (5 mg) and Week 22 (after the donepezil had been discontinued). Measures of cognitive function were administered at each visit, encompassing the following domains: memory; attention; mood; and adaptive functioning. Donepezil was well tolerated at the 2.5 and 5 mg doses. The side effects were mild, transient, and consistent with the adverse events noted with cholinesterase inhibitors. Some children showed improvement on measures of memory (NEPSY Memory for Names and Narrative Memory) and sustained attention to tasks (Conners' Parent Rating Scales), although increased irritability and/or assertiveness were noted in some patients. Overall, this clinical report series adds to our initial findings of language gains in children with DS treated with donepezil. It also supports the need for larger, double-blind studies of the safety and efficacy of donepezil and other cholinesterase inhibitors for children with DS.

Individuals with Down syndrome (DS) have decreased cholinergic function and an uneven profile of cognitive abilities, with more pronounced deficits in learning, memory, and expressive language. Cholinesterase inhibitors may improve cognitive function in adults and adolescents with DS, but studies in children with DS have been limited. This study aimed to: (i) investigate the safety and efficacy of rivastigmine treatment; (ii) build upon our open-label studies in children with DS in a double-blind, placebo-controlled clinical trial; and (iii) investigate specific cognitive domains that may respond to rivastigmine treatment. We conducted a 20-week double-blind, placebo-controlled trial to investigate the safety and efficacy of rivastigmine in 22 children and adolescents with DS aged 10-17 years. Safety measures included reports of adverse events, laboratory parameters, and electrocardiograms. Efficacy measures included parental assessments of adaptive behavior and executive function, and direct measures of language and memory. No group differences were found on safety measures and 22 of 24 participants that passed study screening completed the study. The results did not demonstrate evidence for significant improvement in aspects of cognition, language, or overall function in the children receiving rivastigmine. Our results suggest that rivastigmine is safe and well-tolerated for children and adolescents with DS, but may not be effective for improving performance on the selected measures in this study. However, larger samples and/or alternate measures could possibly reveal improvements in cognitive function with rivastigmine treatment. Further research is needed to define a battery of cognitive measures that is sensitive to treatment effects in DS. © 2016 Wiley Periodicals, Inc.

At present, there is no proven pharmacologic treatment for cognitive or language impairments in Down syndrome (DS). Cholinergic deficits have been documented in DS and linked to cognitive deficits. This study is a 24-week open-label clinical trial of donepezil hydrochloride for the treatment of language deficits in adults with DS. To our knowledge, this is the first prospective study to evaluate systematically the effects of donepezil, a cholinesterase inhibitor, on specific language domains in DS. The main finding that emerged was an improvement in expressive language performance following donepezil therapy. Despite the multiple methodological limitations, the results raise important questions regarding the role of the cholinergic system in language function and the specific effect of cholinergic therapy in the treatment of language impairment in DS. The results support the need for large-scale controlled studies of the effects of donepezil treatment on language and on other cognitive domains in DS.

Editors’ Note: In their article “Cognitive outcome of patients with classic infantile Pompe disease receiving enzyme therapy,” Ebbink et al. reported data consistent with Drs. Spiridigliozzi et al.'s findings that CNS glycogen does not significantly impair cognitive function through the middle childhood years but may be related to delayed processing speed. Drs. Walters et al. report the results of their investigation into possible etiologies behind chocolate consumption lowering stroke risk. Megan Alcauskas, MD, and Robert C. Griggs, MD We would like to inquire whether glycogen …

Fifty-one preschool speech-language screening tests were reviewed with regard to criteria crucial to screening test selection: professional time required, comprehensiveness, norms, and reliability/validity. A rationale was given for specific guidelines for each criterion. Twenty-five of the tests met the criterion of requiring 10 minutes or less. Nine of these met the criteria for brevity and comprehensiveness. Only six of the standardized tests reported any data that could be used to calculate clinical indices required to evaluate screening test validity. Of these six, only two provided the kind of data that would permit calculation of all predictive indices.

This report describes the cognitive development of 17 children with infantile Pompe disease who participated in a 52-week clinical trial of enzyme replacement therapy (ERT) via biweekly infusion of Myozyme® (alglucosidase alfa). Subjects were six months of age or younger (adjusted for gestational age) upon initiation of ERT. The Mental Scale of the Bayley Scales of Infant Development-Second Edition (BSID-II) was administered to obtain a Mental Development Index (MDI) at baseline and weeks 12, 26, 38, and 52 of ERT to assess cognitive development in this treated cohort. Data regarding motor development were also obtained at the same visits and these were used to determine correlations between cognitive and motor development. Over the course of the study, two subgroups of subjects emerged: high responders who were sitting independently and/or ambulating by week 52 (n = 13) and limited responders who showed minimal motor gains throughout the first year of ERT (n = 4). In the high responder group, MDI scores on the BSID-II remained stable throughout the study and were within normal limits. Positive correlations between cognitive and motor development were also present. These data suggest that the cognitive function of infants up to 18 months of age with Pompe disease is unaffected by the possible presence of glycogen in the central nervous system. Continued investigation of the cognitive development of older survivors is warranted.

The effect of input device (touchscreen vs. number keyboard) on preschoolers' vocabulary identification performance at low intensity was examined. Both methods of input were easily learned by preschool children as young as three and one-half years of age. Vocabulary identification performance at a comfortable listening level was equivalent for both groups [keyboard (95%); touchscreen (97%)]. However, as signal intensity increased, the touchscreen group identified the target words at a lower intensity level than the keyboard group. The results indicate that operating a number keyboard can interfere with a preschooler's ability to perform at his/her highest level on computer software, especially when the attention/cognitive demands of the software are high. Thus, when using the computer as a teaching or assessment tool for preschool children or children with cognitive handicaps, a touchscreen or similar direct selection device should be the input mode of choice.

Two cohorts of 4- and 5-year-old children ( N = 700) were screened with the Fluharty Preschool Speech and Language Screening Test. Two stratified samples ( n = 51 cohort 1; n = 147 cohort 2), based on speech-language screening results, were administered criterion tests for articulation (AAPS-R or Templin-Darley) and language (TOLD or TALC-R). Clinical validation indices for combined speech or language outcome in the two cohorts were as follows: sensitivity, .43 and .31 respectively; specificity, .82 and .93; predictive value, .43 and .54; overreferral, 14% and 5%; underreferral, 14% in both cohorts, and percent agreement, 72% and 80%. The measure of sensitivities for language outcomes was lower than the above, whereas sensitivities for articulation was higher. These results suggest that the Fluharty is too insensitive to be relied on for screening programs aimed at identifying preschool children with language disorders, although it appears to have promise for the identification of children with articulation impairments.

The objective of our study was to assess the efficacy and safety of donepezil in young adults with Down syndrome (DS) but no evidence of Alzheimer disease (AD). A 12-week, randomized, double-blind, placebo-controlled study with a 12-week, open-label extension was conducted. The intervention consisted of donepezil (5-10 mg/day) in young adults (aged 18-35 years) with DS, but no AD. The primary measure was the Severe Impairment Battery (SIB) test and secondary measures were the Vineland Adaptive Behavior Scales (VABS), the Rivermead Behavioral Memory Test for Children, and the Clinical Evaluation of Language Fundamentals, Third Edition. At baseline, 123 subjects were randomly assigned treatment with donepezil or placebo. During the double-blind phase, SIB scores improved significantly from baseline in both groups, with no significant between-group differences. During the open-label phase, SIB scores in the original donepezil group remained stable; the original placebo group showed an improvement similar to that seen in the double-blind phase. VABS scores improved for donepezil, but not placebo, during the double-blind phase (observed cases, P = 0.03; last observation carried forward, P = 0.07). Post hoc responder analyses were significant for donepezil using three of five response definitions (P < or = 0.045). Adverse event rates were comparable to AD studies. In this first large-scale, multicenter trial of a pharmacological agent for DS, donepezil appears safe. Efficacy interpretation was limited for the primary measure due to apparent learning/practice and ceiling effects. Outcomes in post hoc analyses suggested efficacy in some, but not all subjects, consistent with phenotypic variability of DS. Additional studies are required to confirm potential benefits of donepezil in this population.

Pompe disease is a rare genetic progressive neuromuscular disorder. The most severe form, infantile Pompe disease, has historically resulted in early mortality, most commonly due to cardiorespiratory failure. Treatment with enzyme replacement therapy (ERT) using alglucosidase alfa (Myozyme(®)) has extended the lifespan of individuals with this disease. With the introduction of ERT and the resultant improved survival, dysphagia is being encountered clinically with increasing regularity though systematic data remain unavailable. We retrospectively studied the oropharyngeal swallowing of 13 infants and children with Pompe disease using videofluoroscopy before initiation of ERT, allowing for baseline swallow function to be established in an untreated cohort. Dysphagia was present in all 13 subjects, even in a participant only 15 days old. Oral stage signs were present in 77%, most frequently a weak suck in 69%. Pharyngeal stage signs were present in 100%, including a pharyngeal swallow delay in 92% and pharyngeal residue in 77%. Airway invasion was present in 76.9% of subjects, including penetration in five (38.46%) and silent aspiration in an additional five (38.46%). No relationship in the relative involvement of swallowing, gross motor function, and cardiac disease appeared to be present.

Individuals with Down syndrome (DS) exhibit a cholinergic deficiency similar to that found in Alzheimer’s disease. Cholinesterase inhibitors, used to treat Alzheimer’s disease, may improve cognitive function in individuals with DS. This is the first investigation of the safety and efficacy of rivastigmine (an acetyl and butyryl cholinesterase inhibitor) on specific cognitive domains in pediatric DS. Eleven subjects with DS (ages 10–17 years) were treated with a liquid formulation of rivastigmine. Four subjects experienced no adverse events (AEs). Seven subjects reported AEs that were mild, transient and consistent with adverse events typically noted with cholinesterase inhibitors. Significant improvements were found in over-all adaptive function (Vineland Adaptive Behavior Scales and Clinician’s Interview-Based Impression of Change), attention (Leiter Attention Sustained tests A and B), memory (NEPSY: Narrative and Immediate Memory for Names subtests) and language (Test of Verbal Expression and Reasoning and Clinical Evaluation of Language Fundamentals–Preschool) domains. Improved language performance was found across all functional levels. These results underscore the need for larger, controlled studies employing a carefully constructed test battery capable of measuring the full scope of performance across multiple domains and a wide range of functional levels.

Clinical and translational research play a key role in the transition of basic research discoveries to effective therapies. In Down syndrome (DS), these research approaches are not well utilized or developed to test new therapies to improve cognitive and/or adaptive function in this population. This article reviews the history of clinical trial research in children with DS from a cognitive research perspective and discusses important issues relevant to the conduct of well designed clinical trials for this population. Specific issues addressed include: funding, study design, study medication, subject recruitment and retention, safety, and efficacy challenges. The Duke Down Syndrome Research Team's program of clinical research of cholinesterase inhibitors for individuals with DS serves as the model application for the identified research principles. It is hoped that this article will raise awareness of the unmet need for clinical research in the cognitive and adaptive function of individuals with DS, especially children with DS.

To the Editor: In earlier pilot studies, we reported improvements in global function [Kishnani et al., 1999] and expressive language function [Heller et al., 2003] in adults with Down syndrome (DS) following cholinergic therapy (donepezil hydrochloride). In this study, we report results of a small open-label clinical trial of donepezil in children with DS. To our knowledge, this is the first study evaluating the effects of donepezil on language in children with DS. After obtaining IRB approval and written informed consent, we enrolled seven children (2M:5F) between the ages of 8 and 13 years (mean age = 10.5 years) with DS (trisomy 21 by blood chromosome analysis) and their primary caregivers in a prospective open trial of donepezil. All subjects were verbal, able to hear speech at a conversational level, and able to ingest oral medication. None of the subjects had active thyroid disease, vitamin B12 deficiency, clinically-confirmed pregnancy, or clinically-significant systemic disorders, (e.g., bradycardia (HR < 50), insulin-dependent diabetes mellitus, active peptic ulcer, celiac disease, significant reactive airways, or seizure disorder) at the time of entry into the trial. They had not previously ingested cholinesterase inhibitors or any other investigational or alternative therapies used to treat the symptoms of DS in the 30 days prior to or during the trial. IQs of six subjects (obtained from school reports) ranged from 46 to 66 (mean IQ = 50). The IQ of one subject could not be determined from records. This 22-week trial (16 week open treatment study followed by a 6-week washout) was completed at the General Clinical Outpatient Research Unit at Duke University Medical Center. Subjects attended four sessions, week 0 (baseline), week 8 (low dose), week 16 (high dose), and week 22 (washout). At the completion of the baseline visit, donepezil was dosed orally at 2.5 mg once daily for 8 weeks. Based on tolerability, the dose was increased to 5 mg daily for the remaining 8 weeks. Subjects were monitored closely for safety by regular phone calls in between scheduled visits. Two language measures were used, the Test of Problem Solving [TOPS, Zachman et al., 1984] and the Clinical Evaluation of Language Fundamentals-3 [CELF-3, Semel et al., 1995]. The CELF-3 was administered at baseline, week 16, and week 22. The TOPS was completed at all four visits. Because the CELF-3 and TOPS have not been standardized for individuals with DS and the subjects’ language performance was significantly below standard age norms, performance-based comparisons were made with raw scores and age equivalencies. The effect of the medication on language performance was measured by change from baseline performance at the week 8 and week 16 assessments. One subject was excluded from all analyses because of a protocol deviation in administered dosage. No patient experienced serious adverse effects or withdrew from the study. Performance comparisons (completed by repeated measure t-tests) were based on a total n of 6 (five subjects for the baseline vs. week 8 TOPS comparison). Due to the preliminary and exploratory nature of the study, we did not correct for multiple comparisons. P values at or below 0.05 (two-tailed) were viewed as significant. Overall, language performance levels were low. The average TOPS age score was below the 3 years 5 months test basal for all sessions, and the average CELF-3 age score was 4 years 3 months at baseline, and 4 years 7 months at week 16. Essentially no change in language performance with treatment was noted on the TOPS at week 8 (the difference between mean baseline and week 8 scores was

Disagreement exists concerning the relationship between the perception of phonetic contrasts and their production by both normal and articulation-delayed children. The perception of three approximant consonant contrasts (/w/-/r/,/w/-/l/, /r/-/1/) was examined in two groups of 3-year-old children: Normal children who did and did not articulate /r/ and /1/ correctly and articulation-delayed children who misarticulated /r/ and /1/. Perception was assessed in a two-choice forced-choice identification task in which the subjects heard a word and pushed a button lighting a picture corresponding to the word. In general, normally developing children were highly accurate in their perception of all three contrasts, but there was more variability in /w/-/1/ perceptual performance among the children who neutralized the/w/-/1/contrast. Articulation-delayed children displayed a wider range of production patterns and were more variable in their perceptual performance than normally developing children. Results suggest that normally developing children learn to perceive approximant contrasts prior to 3 years of age. However, some but not all articulation-delayed 3-year-old children may still make errors in the perception of approximants.