Feasibility, reliability, and clinical validity of the Test of Attentional Performance for Children (KiTAP) in Fragile X syndrome (FXS).

BACKGROUND: Attention and inhibition are core executive-function deficits in FRagile X syndrome (FXS). This pilot study evaluated the feasibility, reproducibility, and clinical relevance of the KiTAP, a computer-based pictorial measure of attention and inhibition with an enchanted-castle theme, in an FXS cohort. METHODS: The 8-subtest KiTAP battery (as many subtests as each could perform) was given to 36 subjects with FXS, of variable age and cognitive/behavioral functioning, and 29 were retested, with an interval of 2 to 4 weeks between sessions. Subjects were rated by parents on the Aberrant Behavior Checklist-Community Edition (ABC-C) and Behavior Assessment System for Children, Second Edition (BASC-2). Feasibility, ceiling and basal effects, and data range and distribution analyses were used to eliminate outliers and invalid data points. Reproducibility of scores was analyzed using intraclass correlation coefficients (ICCs) and validity/clinical relevance was assessed by correlating KiTAP scores with ABC-C and BASC-2 scores. RESULTS: Most of the participants with FXS were able to complete the Alertness, Distractibility, Flexibility, and Go/NoGo subtests.About 50 to 60% completed the Visual Scanning and Vigilance subtests, and 20 to 25% completed the Sustained Attention and Divided Attention subtests. A panel of seven scores from four subtests were identified as feasible for most subjects, lacked excessive ceiling, basal, or learning effects, exhibited an acceptable range and distribution of scores, had good reproducibility (ICC > 0.7), and correlated with behavioral ratings for hyperactivity or attention (P < 0.01). Only minor differences in performance on the KiTAP were seen between mental age-matched cohorts of subjects with FXS and non-FXS intellectual disability. CONCLUSIONS: The KiTAP can be administered to cohorts with FXS over a wide range of function with valid reproducible scores. With additional validation, it could represent a useful outcome measure for assessment of attention/executive-function abilities in clinical trials targeted to these core deficits in FXS.

Clinic-based retrospective analysis of psychopharmacology for behavior in fragile x syndrome.

Fragile X syndrome (FXS) is associated with behavior that limits functioning, including distractibility, hyperactivity, impulsivity, hyperarousal, anxiety, mood dysregulation, and aggression. Medication response and side effect data were reviewed retrospectively for 257 patients (age 14 ± 11 years, range 4-60 years, 203 M, 54 F) attending an FXS clinic. Treatment success rates were defined as the percentage of positive response in the form of documented clinical report of improvement in the behavior(s) being targeted over at least a 6-month period on the medication, without side effects requiring medication discontinuance, while failures were defined as discontinuance of medication due to lack of clinical effectiveness or side effects. Success rate for treatment of targeted behaviors with trials of individual medications was 55% for stimulants, 53% for antidepressants, 62% for alpha2-agonists, and 54% for antipsychotics. With sequential trials of different medications in the same class, success rate improved to 73-77%. Side effect-related failures were highest for antipsychotics. Systematic psychopharmacologic intervention targeted to behavioral symptoms appears helpful in the majority of patients with FXS.

Reversal of fragile X phenotypes by manipulation of AßPP/Aß levels in Fmr1KO mice.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading known genetic cause of autism. Fragile X mental retardation protein (FMRP), which is absent or expressed at substantially reduced levels in FXS, binds to and controls the postsynaptic translation of amyloid ß-protein precursor (AßPP) mRNA. Cleavage of AßPP can produce ß-amyloid (Aß), a 39-43 amino acid peptide mis-expressed in Alzheimer's disease (AD) and Down syndrome (DS). Aß is over-expressed in the brain of Fmr1(KO) mice, suggesting a pathogenic role in FXS. To determine if genetic reduction of AßPP/Aß rescues characteristic FXS phenotypes, we assessed audiogenic seizures (AGS), anxiety, the ratio of mature versus immature dendritic spines and metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD) in Fmr1(KO) mice after removal of one App allele. All of these phenotypes were partially or completely reverted to normal. Plasma Aß(1-42) was significantly reduced in full-mutation FXS males compared to age-matched controls while cortical and hippocampal levels were somewhat increased, suggesting that Aß is sequestered in the brain. Evolving therapies directed at reducing Aß in AD may be applicable to FXS and Aß may serve as a plasma-based biomarker to facilitate disease diagnosis or assess therapeutic efficacy.

Targeted treatments for fragile X syndrome.

Fragile X syndrome (FXS) is the most common identifiable genetic cause of intellectual disability and autistic spectrum disorders (ASD), with up to 50% of males and some females with FXS meeting criteria for ASD. Autistic features are present in a very high percent of individuals with FXS, even those who do not meet full criteria for ASD. Recent major advances have been made in the understanding of the neurobiology and functions of FMRP, the FMR1 (fragile X mental retardation 1) gene product, which is absent or reduced in FXS, largely based on work in the fmr1 knockout mouse model. FXS has emerged as a disorder of synaptic plasticity associated with abnormalities of long-term depression and long-term potentiation and immature dendritic spine architecture, related to the dysregulation of dendritic translation typically activated by group I mGluR and other receptors. This work has led to efforts to develop treatments for FXS with neuroactive molecules targeted to the dysregulated translational pathway. These agents have been shown to rescue molecular, spine, and behavioral phenotypes in the FXS mouse model at multiple stages of development. Clinical trials are underway to translate findings in animal models of FXS to humans, raising complex issues about trial design and outcome measures to assess cognitive change that might be associated with treatment. Genes known to be causes of ASD interact with the translational pathway defective in FXS, and it has been hypothesized that there will be substantial overlap in molecular pathways and mechanisms of synaptic dysfunction between FXS and ASD. Therefore, targeted treatments developed for FXS may also target subgroups of ASD, and clinical trials in FXS may serve as a model for the development of clinical trial strategies for ASD and other cognitive disorders.

Reliability of eye tracking and pupillometry measures in individuals with fragile X syndrome.

Recent insight into the underlying molecular and cellular mechanisms of fragile X syndrome (FXS) has led to the proposal and development of new pharmaceutical treatment strategies, and the initiation of clinical trials aimed at correcting core symptoms of the developmental disorder. Consequently, there is an urgent and critical need for outcome measures that are valid for quantifying specific symptoms of FXS and that are consistent across time. We used eye tracking to evaluate test-retest reliability of gaze and pupillometry measures in individuals with FXS and we demonstrate that these measures are viable options for assessing treatment-specific outcomes related to a core behavioral feature of the disorder.

Effect of Anticoagulants on Amyloid ß-Protein Precursor and Amyloid Beta Levels in Plasma.

Altered levels of amyloid ß-protein precursor (AßPP) and/or amyloid beta (Aß) are characteristic of several neurological disorders including Alzheimer's disease (AD), Down syndrome (DS), Fragile X syndrome (FXS), Parkinson's disease (PD), autism and epilepsy. Thus, these proteins could serve as valuable blood-based biomarkers for assessing disease severity and pharmacological efficacy. We have observed significant differences in Aß1-42 levels in human plasma dependent on the anticoagulant utilized during blood collection. Our data suggests that anticoagulants alter AßPP processing and that care needs to be used in comparing published studies that have not utilized the same blood collection methodology.

Prepulse inhibition in fragile X syndrome: feasibility, reliability, and implications for treatment.

Pharmacological rescue of behavioral, cognitive and synaptic abnormalities in the animal models of fragile X syndrome (FXS) has prompted the initiation of clinical trials of targeted treatments in humans with this condition. Objective, well-validated outcome measures that are reflective of FXS deficits and can be modeled similarly in animal and human studies are urgently needed. A protocol measuring prepulse inhibition (PPI) of the startle reflex, including measures of test-retest stability, was evaluated in 61 individuals with the fragile X full mutation (40 males and 21 females; 19.18 +/- 7.18 years) and 63 age-matched normal controls (35 males and 28 females; 20.83 +/- 6.96 years) across two laboratory sites with identical equipment and protocols. Relative to controls, the fragile X group had PPI impairment of 26%, 22%, and 28% for 60, 120, and 240 ms prepulse interval trial types, respectively, P = 0.000002. PPI test-retest reliability in 29 of the participants was excellent for the 120 ms prepulse interval trials (intraclass correlations: FXS, 0.85; controls, 0.88, 0.89 overall). This study demonstrates the feasibility and reliability of PPI measurement in a developmentally disabled population and highlights its potential as an outcome measure to test the efficacy of targeted neurotherapeutic agents.

Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome.

OBJECTIVE: In fragile X syndrome (FXS), it is hypothesized that absence of the fragile X mental retardation protein (FMRP) disrupts regulation of group 1 metabotropic glutamate receptor (mGluR and mGluR5)-dependent translation in dendrites. Lithium reduces mGluR-activated translation and reverses phenotypes in the dfxr mutant fly and fmr1 knockout mouse. This pilot add-on trial was conducted to evaluate safety and efficacy of lithium in humans with FXS. METHODS: Fifteen individuals with FXS, ages 6-23, received lithium titrated to levels of 0.8-1.2 mEq/L. The primary outcome measure, the Aberrant Behavior Checklist --Community Edition (ABC-C) Irritability Subscale, secondary outcome measures (other ABC-C subscales, clinical global improvement scale (CGI), visual analog scale for behavior (VAS), Vineland Adaptive Behavior Scale (VABS)), exploratory cognitive and psychophysiological measures and an extracellular signal-regulated kinase (ERK) activation assay were administered at baseline and 2 months of treatment. Side effects were quantified with a standardized checklist and lithium level, complete blood count (CBC), thyroid stimulating hormone (TSH), and chemistry screen were done at baseline, 2 weeks, 4 weeks and 2 months. RESULTS: The only significant treatment-related side effects were polyuria/polydipsia (n = 7) and elevated TSH (n = 4). Although the ABC-C Irritability Subscale showed only a trend toward improvement, there was significant improvement in the Total ABC-C score (p = 0.005), VAS (p = 0.003), CGI (p = 0.002), VABS Maladaptive Behavior Subscale (p = 0.007), and RBANS List Learning (p = 0.03) and an enhanced ERK activation rate (p = 0.007). Several exploratory tasks proved too difficult for lower-functioning FXS subjects. CONCLUSIONS: Results from this study are consistent with results in mouse and fly models of FXS, and suggest that lithium is well-tolerated and provides functional benefits in FXS, possibly by modifying the underlying neural defect. A placebo-controlled trial of lithium in FXS is warranted.