Faculty Bibliography

Importance:Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. Objective:To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. Design, Setting, and Participants:This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. Main Outcomes and Measures:Diagnosis of Alzheimer disease. Results:A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. Conclusions and Relevance:While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

Persistent post-traumatic headache (PPTH) is often the most common injury post mild traumatic brain injury (mTBI), reported by 47%-95% of patients. Progressive muscle relaxation (PMR) has level A evidence in preventing migraine and tension headaches. However, research on this behavioral therapy for PPTH, let alone smartphone-delivered, is limited. We performed a single-arm study of prospective patients calling our Concussion Center between June 2017-July 2018. Inclusion criteria were that subjects had to meet ICHD-3 criteria for PPTH secondary to mTBI, have four or more headache days a month, be age 18-85 and 3-12 months post injury, own a smartphone and not tried headache behavioral therapy within the year. We recorded baseline headache and neuropsychiatric data. Using the RELAXaHEAD smartphone application, which has a headache diary and PMR audio files, participants were instructed to record headache symptoms and practice 20 minutes of PMR daily. There were three monthly follow-up assessments. There were 49 subjects enrolled. Basic demographics were: 33 (67%) female with mean age 40.1±14.6 [20,75]. Of the 49 subjects, 15 (31%) had pre-existing headaches. In 11 (22%) subjects, mTBI was sports-related. Subjects reported 17.7±9.3 [4,31] headache days in the month before enrollment, and 49 (100%) experienced over three concussion symptoms. Participants inputted data in the RELAXaHEAD app on average 18.3±12.0 days [0,31] the first month. Number of participants who did PMR over 4 times/week was 12 (24.5%) the first month, 9 (22.5 %) the second month, and 6 (15%) the third month. After three months, 17 (42.5 %) participants continued doing PMR. Participants cited time constraints, forgetfulness, application glitches and repetitiveness as obstacles to practicing PMR. It is feasible to get PPTH subjects to practice behavioral therapy through low-cost smartphone-based PMR two times weekly. Future work will assess efficacy and examine how to optimize barriers to PMR.

Objective: A recent clinical trial with 0.7mg/kg/day of fenfluramine (FFA) showed 62.3% (IC 95%: -47.7%; -72.8%; p<0.001) reduction in convulsive seizure frequency (CSF) compared to placebo. However, the impact of the disease on the patient and their caregivers may depend on other variables. This alternative analysis value the impact of other results.
Method(s): After a baseline period of 6 weeks patients with DS ages 2 to 18 years, was randomized to FFA 0.7 or 0.2mg/kg/day or placebo added. Time to new event (time required to experience the same number of crisis as in the reference period [TTE]) was analyzed. Intervals without crisis and number of days without crisis was analyzed too.
Result(s): 119 patients with DS receiving FFA 0.7mg/kg/day; FFA0.2mg/kg/day; or placebo. TTE was significantly longer in active groups. Placebo: 6 weeks, FFA 0.2mg/kg/day:8 weeks and FFA 0.7mg/kg/day: >12 weeks (p<0.001; ~60% of patients in the FFA 0.7mg/kg/day group never reached their baseline seizure count and were censored). The number of days without crisis was higher in groups treated with FFA: 33 and 20 days without additional crisis counted in the active groups. The longest average without crisis was higher with FFA 0.7mg/kg/day (25 days; p<0.001) and FFA 0.2mg/kg/day (15 days; Px0.035) than with placebo (9.5 days).
Conclusion(s): FFA extended TTE and provided significantly more days without crisis and longer periods without crisis than placebo. Our analysis can help assess the ability of a treatment to reduce the burden of seizures in patients with SD and their caregivers

BACKGROUND AND PURPOSE/OBJECTIVE:Coronavirus disease 2019 (COVID-19) appears to be an independent risk factor for stroke. We hypothesize that patients who develop stroke while hospitalized for severe COVID-19 will have higher inflammatory markers and distinct stroke imaging patterns compared with patients positive for COVID-19 with out-of-hospital stroke onset and milder or no COVID-19 symptoms. MATERIALS AND METHODS/METHODS:This is a retrospective case series of patients positive for COVID-19 on polymerase chain reaction testing with imaging-confirmed stroke treated within a large health care network in New York City and Long Island between March 14 and April 26, 2020. Clinical and laboratory data collected retrospectively included complete blood counts and creatinine, alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin, and D-dimer levels. All CT and MR imaging studies were independently reviewed by 2 neuroradiologists who recorded stroke subtype and patterns of infarction and intracranial hemorrhage. RESULTS:< .003). CONCLUSIONS:Patients with stroke hospitalized with severe COVID-19 are characterized by higher inflammatory, coagulopathy, and tissue-damage biomarkers, supporting proposed pathogenic mechanisms of hyperinflammation activating a prothrombotic state. Cautious balancing of thrombosis and the risk of hemorrhagic transformation is warranted when considering anticoagulation.