Faculty Bibliography

Background: The importance of informant history in the diagnosis of mild cognitive impairment (MCI) has been emphasized. Yet, there is limited literature looking into the agreement of self- and informant- reported memory loss in MCI due to Alzheimer's disease (AD) versus cerebrovascular disease (CVD). We investigated the hypothesis that rates of concordance and discordance differ based on MCI etiology.
Method(s): Retrospective clinical data was gathered from the National Alzheimer's Coordinating Center dataset. First visits with a clinical diagnosis of MCI with a primary etiology of AD without CVD (AD MCI) or CVD without AD (CVD MCI) were included for analysis. Self- and informant-based report of memory loss were gleaned from the questions "does the subject report a decline in memory (relative to previously attained abilities?)" and "does the co-participant report a decline in subject's memory (relative to previously attained abilities?)." We excluded participants with missing self-reported or co-participant information on cognitive decline. Statistical analysis was performed using Chi-squared tests.
Result(s): A total of 1917 AD MCI and 213 CVD MCI visits from unique participants were included in the study. Compared to CVD MCI, AD MCI had a higher incidence of visits where both participant and informant noted memory loss (67.8% vs. 54.0%, p<0.0001). Compared to AD MCI, CVD MCI featured more disagreement between participant and informant, both in cases where the participant denied memory loss (17.8% vs. 12.0%, p = 0.0137) and where the informant denied memory loss (21.6% vs. 11.4%, p < 0.0001). Incidence of both participant and informant denying memory loss were similar between AD MCI and CVD MCI (8.9% vs. 6.6%, p = 0.2580).
Conclusion(s): Self- and collateral-based report of memory loss are more discordant in CVD MCI versus AD MCI. This reinforces the importance of eliciting a history from both patients and reliable informants, especially in patients with vascular risk factors and comorbidities

The utility of the Victoria Symptom Validity Test (VSVT) as a performance validity test (PVT) has been primarily established using response accuracy scores. However, the degree to which response latency may contribute to accurate classification of performance invalidity over and above accuracy scores remains understudied. Therefore, this study investigated whether combining VSVT accuracy and response latency scores would increase predictive utility beyond use of accuracy scores alone. Data from a mixed clinical sample of 163 patients, who were administered the VSVT as part of a larger neuropsychological battery, were analyzed. At least four independent criterion PVTs were used to establish validity groups (121 valid/42 invalid). Logistic regression models examining each difficulty level revealed that all VSVT measures were useful in classifying validity groups, both independently and when combined. Individual predictor classification accuracy ranged from 77.9 to 81.6%, indicating acceptable to excellent discriminability across the validity indices. The results of this study support the value of both accuracy and latency scores on the VSVT to identify performance invalidity, although the accuracy scores had superior classification statistics compared to response latency, and mean latency indices provided no unique benefit for classification accuracy beyond dimensional accuracy scores alone.

OBJECTIVE/UNASSIGNED:Little is known about psychiatric symptoms among patients with migraine and newly diagnosed focal epilepsy. The investigators compared symptoms of depression, anxiety, and suicidality among people with newly diagnosed focal epilepsy with migraine versus without migraine. METHODS/UNASSIGNED:The Human Epilepsy Project is a prospective multicenter study of patients with newly diagnosed focal epilepsy. Depression (measured with the Center for Epidemiologic Studies Depression Scale), anxiety (measured with the 7-item Generalized Anxiety Disorder scale), and suicidality scores (measured with the Columbia-Suicide Severity Rating Scale [C-SSRS]) were compared between participants with versus without migraine. Data analysis was performed with the Kolmogorov-Smirnov test for normality assessment, the Mann-Whitney U test, chi-square test, and linear regression. RESULTS/UNASSIGNED:Of 349 patients with new-onset focal epilepsy, 74 (21.2%) had migraine. There were no differences between the patients without migraine versus those with migraine in terms of age, race, and level of education. There were more women in the group with migraine than in the group without migraine (75.7% vs. 55.6%, p=0.0018). The patients with epilepsy and comorbid migraine had more depressive symptoms than the patients with epilepsy without migraine (35.2% vs. 22.7%, p=0.031). Patients with epilepsy with comorbid migraine had more anxiety symptoms than patients with epilepsy without migraine, but this relation was mediated by age in logistic regression, with younger age being associated with anxiety. Comorbid migraine was not associated with C-SSRS ideation or behavior. CONCLUSIONS/UNASSIGNED:Among a sample of patients with newly diagnosed focal epilepsy, 21.2% had migraine. Migraine comorbidity was associated with higher incidence of depressive symptoms. Future studies should be performed to better assess these relationships and possible treatment implications.

Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 "trios" (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10^-4). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C Both RYR2 mutations are pathogenic (P = 1.7 × 10^-7) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon (P = 1.0 × 10^-7) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts.

BACKGROUND:Our objective was to characterize the frequency, early impact, and risk factors for neurological manifestations in hospitalized children with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or multisystem inflammatory syndrome in children (MIS-C). METHODS:Multicenter, cross-sectional study of neurological manifestations in children aged <18 years hospitalized with positive SARS-CoV-2 test or clinical diagnosis of a SARS-CoV-2-related condition between January 2020 and April 2021. Multivariable logistic regression to identify risk factors for neurological manifestations was performed. RESULTS:Of 1493 children, 1278 (86%) were diagnosed with acute SARS-CoV-2 and 215 (14%) with MIS-C. Overall, 44% of the cohort (40% acute SARS-CoV-2 and 66% MIS-C) had at least one neurological manifestation. The most common neurological findings in children with acute SARS-CoV-2 and MIS-C diagnosis were headache (16% and 47%) and acute encephalopathy (15% and 22%), both P < 0.05. Children with neurological manifestations were more likely to require intensive care unit (ICU) care (51% vs 22%), P < 0.001. In multivariable logistic regression, children with neurological manifestations were older (odds ratio [OR] 1.1 and 95% confidence interval [CI] 1.07 to 1.13) and more likely to have MIS-C versus acute SARS-CoV-2 (OR 2.16, 95% CI 1.45 to 3.24), pre-existing neurological and metabolic conditions (OR 3.48, 95% CI 2.37 to 5.15; and OR 1.65, 95% CI 1.04 to 2.66, respectively), and pharyngeal (OR 1.74, 95% CI 1.16 to 2.64) or abdominal pain (OR 1.43, 95% CI 1.03 to 2.00); all P < 0.05. CONCLUSIONS:In this multicenter study, 44% of children hospitalized with SARS-CoV-2-related conditions experienced neurological manifestations, which were associated with ICU admission and pre-existing neurological condition. Posthospital assessment for, and support of, functional impairment and neuroprotective strategies are vitally needed.

BACKGROUND:The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United States, Chile, and Peru has not been known. METHODS:In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru. RESULTS:A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose. CONCLUSIONS:AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.).