Amanda G. Smith

An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome

BackgroundMinocycline, a member of the tetracycline family, has a low risk of adverse effects and an ability to improve behavioral performance in humans with cognitive disruption. We performed a single-arm open-label trial in which 25 children diagnosed with Angelman syndrome (AS) were administered minocycline to assess the safety and tolerability of minocycline in this patient population and determine the drug’s effect on the cognitive and behavioral manifestations of the disorder.MethodsParticipants, age 4-12 years old, were randomly selected from a pool of previously screened children for participation in this study. Each child received 3 milligrams of minocycline per kilogram of body weight per day for 8 weeks. Participants were assessed during 3 study visits: baseline, after 8-weeks of minocycline treatment and after an 8-week wash out period. The primary outcome measure was the Bayley Scales of Infant and Toddler Development 3rd Edition (BSID-III). Secondary outcome measures included the Clinical Global Impressions Scale (CGI), Vineland Adaptive Behavior Scales 2nd Edition (VABS-II), Preschool Language Scale 4th Edition (PLS-IV) and EEG scores. Observations were considered statistically significant if p < 0.05 using ANOVA and partial eta squared (η2) was calculated to show effect size. Multiple comparisons testing between time points were carried out using Dunnett’s post hoc testing.ResultsSignificant improvement in the mean raw scores of the BSID-III subdomains communication and fine motor ability as well as the subdomains auditory comprehension and total language ability of the PLS-IV when baseline scores were compared to scores after the washout period. Further, improvements were observed in the receptive communication subdomain of the VABS-II after treatment with minocycline. Finally, mean scores of the BSID-III self-direction subdomain and CGI scale score were significantly improved both after minocycline treatment and after the wash out period.ConclusionThe clinical and neuropsychological measures suggest minocycline was well tolerated and causes improvements in the adaptive behaviors of this sample of children with Angelman syndrome. While the optimal dosage and the effects of long-term use still need to be determined, these findings suggest further investigation into the effect minocycline has on patients with Angelman syndrome is warranted.Trial registrationNCT01531582 – clinicaltrials.gov

Topiramate Overdose: A Case Report and Literature Review

Topiramate is a medication introduced in the United States in 1997 for the treatment of epilepsy. Studies are currently underway to determine its effectiveness in the treatment of multiple conditions including bipolar disorder. It is generally well tolerated at doses commonly used in the clinical setting, however, there is little information regarding its safety in overdose. We report the case of a 24-year-old woman who ingested 4000 mg of topiramate in a suicide attempt. She was asymptomatic following the overdose and did not develop any adverse sequelae. In this article we will discuss the commonly seen side effects of topiramate use and examine the available data concerning topiramate overdose. We will review recommendations for the management of such an overdose.

Prader-Willi syndrome--a case report of the multidisciplinary management of the orofacial problems.

A 24-year-old man with Prader-Willi syndrome presented with a class III malocclusion, featuring maxillary hypoplasia and severe enamel deficiency. Treatment involved orthodontic alignment, surgical advancement of the maxilla and restorative treatment to augment vertical facial height, improve the final occlusion and increase short clinical dental crown heights. The principal features of the syndrome and the management of this case are discussed.

Behavioral problems in dementia. Strategies for pharmacologic and nonpharmacologic management.

PREVIEW Behavioral disturbances in Alzheimers disease and related disorders are common throughout all stages of these dementing illnesses. They are a major source of caregiver distress and can lead to premature institutionalization of the patient if not properly addressed. Fortunately, such behaviors are often treatable. In this article, Dr Smith outlines ways to manage behavioral problems in dementia with pharmacologic as well as nonpharmacologic approaches. Throughout, she emphasizes that proper treatment of problem behaviors in this vulnerable population requires the education and patience of caregivers and physicians alike.

Spatial and Temporal Silencing of the Human Maternal UBE3A gene

Angelman syndrome (AS) is characterized by severe cognitive disruption, seizures, difficulty speaking and ataxia. Nearly all cases are attributed to the disruption or absence of the imprinted maternal copy of UBE3A, transcribing an E3-type ubiquitin ligase. Much of what is known about the molecular and biochemical changes in the CNS associated with AS has been obtained through this murine model. This widely used mouse model created by a null mutation of the maternal UBE3A gene recapitulates the major phenotypes characteristic of AS patients. The imprinting of maternal UBE3A was originally believed to be brain region specific; however recent reports using the AS mouse model have revealed a more wide-spread absence of the protein. The present study is the first to determine that the Ube3a protein ablation seen in the AS mouse model is also characteristic of AS patients and the silencing of the paternal UBE3A allele appears to be lifelong.

Identifying Cost-Effective Predictive Rules of Amyloid-β Level by Integrating Neuropsychological Tests and Plasma-Based Markers

BACKGROUND Detecting participants who are positive for amyloid-β (Aβ) pathology is germane in designing prevention trials by enriching for those cases that are more likely to be amyloid positive. Existing brain amyloid measurement techniques, such as the Pittsburgh Compound B-positron emission tomography and cerebrospinal fluid, are not reasonable first-line approaches limited by either feasibility or cost. OBJECTIVE We aimed to identify simple and cost-effective rules that can predict brain Aβ level by integrating both neuropsychological measurements and blood-based markers. METHOD Several decision tree models were built for extracting the predictive rules based on the Alzheimers Disease Neuroimaging Initiative cohort. RESULTS We successfully extracted predictive rules of Aβ level. For cognitive function variables, cases above the 45th percentile in total cognitive score (TOTALMOD), above the 52nd percentile of delayed word recall, and above the 70th percentile in orientation resulted in a group that was highly enriched for amyloid negative cases. Conversely scoring below the 15th percentile of TOTALMOD resulted in a group highly enriched for amyloid positive cases. For blood protein markers, scoring below the 57th percentile for apolipoprotein E (ApoE) levels (irrespective of genotype) enriched two fold for the risk of being amyloid positive. In the high ApoE cases, scoring above the 60th percentile for transthyretin resulted in a group that was >90% amyloid negative. A third decision tree using both cognitive and blood-marker data slightly improved the classification of cases. CONCLUSION Our study demonstrated that the integration of the neuropsychological measurements and blood-based markers significantly improved prediction accuracy. The prediction model has led to several simple rules, which have a great potential of being naturally translated into clinical settings such as enrichment screening for AD prevention trials of anti-amyloid treatments.

UTILIZING A MOBILE CLINICAL TRIAL UNIT TO ENHANCE RECRUITMENT IN PREVENTION TRIALS FOR ALZHEIMER’S DISEASE

persons could be screened at an event. Ultimately 461 were screened, and 68 randomized. Study 2 (Target ApoE4 homozygotes): We redesigned our AD prevention educational events to combine group education with genotype swabbing. These events, supplemented by referrals from the GeneMatch program, identified 30 persons in the first 12 months referred to Banner Alzheimer’s Institute for genetic disclosure. 4/6 community members randomized, and 6/21 GeneMatch referrals randomized. Conclusions: Recruitment in the preclinical space will require continual experimentation with novel approaches to identify best practices. Strategies which target the age range of interest and recruit in the context of an educational setting seem promising.

ENHANCING FLORIDA CLINICAL TRIAL RECRUITMENT IN ALZHEIMER'S DISEASE RESEARCH THROUGH A MOBILE CLINICAL TRIAL UNIT

Background:Florida has a large number of senior residential communities and an excellent series of state-supported Memory Disorders Clinics (MDCs) through the Alzheimer’s Disease Initiative. Although these clinics care for 10,000 memory-impaired cases annually, many do not have the resources or expertise to offer clinical research. Participant enrollment and retention is also impacted by problems in transportation to the clinical trial sites where patients may travel an hour or more to access the nearest clinical trial in Florida.Methods:The Byrd Alzheimer’s Institute has developed a mobile Alzheimer’s clinical trial unit that will offer potential benefits including: A) increasing the availability of Alzheimer’s clinical research, B) taking advantage of the clinical diagnosis provided by MDCs for recruitment, and C) increasing the number of clinical trial participants evaluated by the same individuals. This mobile unit could travel to retirement communities and/or MDCs that lack established facilities to conduct clinical trial research. The increased accessibility may increase long term retention of research subjects. Results:Our facility has acquired funding from the State of Florida in July 2015. As of January 2016, manufacturing has begun. Final unit delivery is expected May 2016. The mobile unit model includes: reception, exam room, two consultation/testing rooms, and a phlebotomy suite. We estimate ability to conduct 5-8 study visits daily with a team of study physician, study nurse, and two clinical raters. The unit will visit approximately 2 sites per week on a rotating schedule. Conclusion: The mobile unit provides multi-center recruitment/enrollment equal to activity of 4-5 clinical research centers. It offers sponsors the benefit of having single site for monitoring, contracts, and qualified staff to reduce variability of research data and outcome measures collected. It offers the benefit of reduced travel to potential participants and research opportunities otherwise not be available to them. We project the enrollment capability on this mobile unit for a clinical trial to be 75-100 participants, in phased enrollment across multiple locations over a period of time. We expect that sites will be located within 90 minutes of the Institute, including Sarasota, Orlando, and St. Petersburg areas, which offer diverse communities of African Americans and Hispanics.

Identifying biomarkers of dementia prevalent among amnestic mild cognitively impaired ethnic female patients.

BackgroundThere is a need to investigate biomarkers that are indicative of the progression of dementia in ethnic patient populations. The disparity of information in these populations has been the focus of many clinical and academic centers, including ours, to contribute to a higher success rate in clinical trials. In this study, we have investigated plasma biomarkers in amnestic mild cognitively impaired (aMCI) female patient cohorts in the context of ethnicity and cognitive status.MethodA panel of 12 biomarkers involved in the progression of brain pathology, inflammation, and cardiovascular disorders were investigated in female cohorts of African American, Hispanic, and White aMCI patients. Both biochemical and algorithmic analyses were applied to correlate biomarker levels measured during the early stages of the disease for each ethnicity.ResultsWe report elevated plasma Aβ40, Aβ42, YKL-40, and cystatin C levels in the Hispanic cohort at early aMCI status. In addition, elevated plasma Aβ40 levels were associated with the aMCI status in both White and African American patient cohorts by the decision tree algorithm. Eotaxin-1 levels, as determined by the decision tree algorithm and biochemically measured total tau levels, were associated with the aMCI status in the African American cohort.ConclusionsOverall, our data displayed novel differences in the plasma biomarkers of the aMCI female cohorts where the plasma levels of several biomarkers distinguished between each ethnicity at an early aMCI stage. Identification of these plasma biomarkers encourages new areas of investigation among aMCI ethnic populations, including larger patient cohorts and longitudinal study designs.