Faculty Bibliography

Propagation of tau pathology via the seeding of naive tau aggregation underlies the progression of Alzheimer's disease (AD) and related tauopathies. Individuals with Down syndrome (DS) develop tau pathology at the fourth decade of life, but tau seeding activity in DS brain has not yet been determined. To measure tau seeding activity, we developed capture assay and seeded-tau aggregation assay with truncated tau_151-391. By using brain extracts from AD and related tauopathies, we validated these two methods and found that the brain extracts from AD and related tauopathies, but not from controls and the diseases in which tau was not hyperphosphorylated, captured in vitro and seeded 3R-tau_151-391 and 4R-tau_151-391 to aggregate in cultured cells similarly. Captured tau_151-391 levels were strongly correlated with the seeded-tau_151-391 aggregation. Employing these two newly developed assays, we analyzed tau seeding activity in the temporal (TC), frontal (FC), and occipital cortex (OC); corpus callosum (CC); and cerebellar cortex (CBC) of DS and control brains. We found that the extracts of TC, FC, or OC, but not the CC or CBC of DS or the corresponding brain regions of control cases, captured tau_151-391. Levels of the captured tau_151-391 by brain extracts were positively correlated with their levels of phosphorylated tau. Extracts of cerebral cortex and CC, but not CBC of DS with a similar tau level, induced more tau_151-391 aggregation than did the corresponding samples from the control cases. Thus, higher tau seeding activity associated with tau hyperphosphorylation was found in the TC, FC, and OC of DS compared with the corresponding control regions as well as with the CBC and CC of DS. Of note, these two assays are sensitive, specific, and repeatable at a low cost and provide a platform for measuring tau seeding activity and for drug screening that targets tau propagation.

OBJECTIVE:Morphological and angioarchitectural features of cerebral arteriovenous malformations (AVMs) have been widely described and associated with outcomes; however, few studies have conducted a quantitative analysis of AVM flow. The authors examined brain AVM flow and transit time on angiograms using direct visual analysis and a computer-based method and correlated these factors with the obliteration response after Gamma Knife radiosurgery. METHODS:A retrospective analysis was conducted at a single institution using a prospective registry of patients managed from January 2013 to December 2019: 71 patients were analyzed using a visual method of flow determination and 38 were analyzed using a computer-based method. After comparison and validation of the two methods, obliteration response was correlated to flow analysis, demographic, angioarchitectural, and dosimetric data. RESULTS:The mean AVM volume was 3.84 cm3 (range 0.64-19.8 cm3), 32 AVMs (45%) were in critical functional locations, and the mean margin radiosurgical dose was 18.8 Gy (range 16-22 Gy). Twenty-seven AVMs (38%) were classified as high flow, 37 (52%) as moderate flow, and 7 (10%) as low flow. Complete obliteration was achieved in 44 patients (62%) at the time of the study; the mean time to obliteration was 28 months for low-flow, 34 months for moderate-flow, and 47 months for high-flow AVMs. Univariate and multivariate analyses of factors predicting obliteration included AVM nidus volume, age, and flow. Adverse radiation effects were identified in 5 patients (7%), and 67 patients (94%) remained free of any functional deterioration during follow-up. CONCLUSIONS:AVM flow analysis and categorization in terms of transit time are useful predictors of the probability of and the time to obliteration. The authors believe that a more quantitative understanding of flow can help to guide stereotactic radiosurgery treatment and set accurate outcome expectations.

Harsh parental discipline is ineffective and potentially harmful to children, yet it is still common, particularly in many African countries. Culturally responsive education programs are needed to shift parenting practices in African countries, but there is limited baseline research to inform such efforts. This study"™s objectives were to establish the baseline prevalence of harsh physical discipline practices among primary caregivers of pre-school children in Ethiopia and to identify associated factors to inform intervention efforts. The well-established Parent"“Child Conflict Tactics Scale section on physical assault was translated and administered to primary caregivers of 1139 pre-school children aged 4"“6 years sampled from four regions of Ethiopia. Trained interviewers also collected basic socio-demographic data. Based on caregiver report, 52.5% (n = 598) of the children had experienced harsh physical discipline and an additional 12.7% (n = 145) experienced moderate physical discipline in their lifetimes. After controlling for covariates, the factors significantly related to increased likelihood of harsh discipline were geographic region, female caregivers, lack of employment, at least moderate perceived social status, and non-Muslim religion. These data establish a baseline from which to evaluate the impact of future educational interventions designed to shift practices. Information about the correlates can be used to tailor such intervention efforts toward those most likely to use harsh discipline practices.

Clinical studies of rescue medications for seizure clusters are limited and designed to satisfy regulatory requirements, which may not fully consider the needs of the diverse patient population that experiences seizure clusters or utilize rescue medication. The purpose of this narrative review is to examine factors that contribute to, or may influence the quality of, seizure cluster research with a goal of improving clinical practice. We address five areas of unmet needs and provide advice of how they could enhance future trials of seizure cluster treatments. The topics addressed in this manuscript are: 1) unaddressed endpoints to pursue in future studies, 2) roles for devices to enhance rescue medication clinical development programs, 3) tools to study seizure cluster prediction and prevention, 4) the value of other designs for seizure cluster studies, and 5) unique challenges of future trial paradigms for seizure clusters. By focusing on novel endpoints and technologies with value to patients, caregivers, and clinicians, data obtained from future studies can benefit the diverse patient population that experiences seizure clusters, providing more effective, appropriate care as well as alleviating demands on healthcare resources.

Purpose: DS is a severe and progressive genetic epilepsy that is generally caused by spontaneous, heterozygous loss of function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel subunit type 1 alpha (Nav1.1). STK-001 is an investigational ASO designed to upregulate Nav1.1 protein expression in brain by leveraging the wild-type (non-mutant) copy of SCN1A to restore physiological Nav1.1 levels, thereby potentially reducing seizure frequency (SF) and non-seizure comorbidities.
Method(s): Patients (N = 22) with DS were grouped by age (2-12 and 13-18 years) and SF was evaluated for 28 days before CSF collection (baseline). During the pre-treatment period, patients had a high rate of convulsive SF (median = 16). STK-001 was administered intrathecally on Day 1 as a single dose (SAD: 10, 20, or 30mg) or on Day 1, Week 4 and Week 8 as multiple ascending doses (MAD: 20mg).
Result(s): 20/22 patients were taking >=3 concomitant anti-seizure medicines as maintenance therapy, and 16/22 were taking >=4. Adverse events (AEs), SF, and plasma PK were monitored throughout. At datacut, 4 patients had study drug-related treatment-emergent (TE) AEs; none in 30mg SAD and 1 in the 20mg MAD cohorts. Five patients had serious TEAEs, none related to study drug. In addition, 12/17 SAD patients experienced a reduction in convulsive SF from Day 1 to Days 29-84, including 7/7 in the 2-12 years age group. Dose-dependent increases in plasma exposure were observed and STK-001 could be measured in the CSF up to 6 months post single intrathecal dose.
Conclusion(s): Single doses of STK-001 up to 30mg, and three 20mg doses of STK-001 given every four weeks, were well-tolerated with no study drug-related safety concerns observed. This MONARCH data analysis provides positive safety and PK data and evidence of seizure reduction, supporting continued development of STK-001 as the first disease-modifying precision medicine for DS