Faculty Bibliography

BACKGROUND:Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is characterized by progressive memory loss and cognitive impairment. Our understanding of AD pathogenesis is limited and no effective disease-modifying treatment is available. Mitochondria are cytoplasmic organelles critical to the homeostatic regulation of glucose and energy in the cell. METHODS:Mitochondrial abnormalities are found early in the course of AD and dysfunctional mitochondria are involved in AD progression. The resulting respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species are highly damaging to neurons. Restoration of mitochondrial function may provide a novel therapeutic strategy for AD. RESULTS:This review discusses the specifics of mitochondrial fragmentation, imbalances in fission and fusion, and DNA damage seen in AD and the contribution of compromised mitochondrial activity to AD etiopathogenesis. It explores how an understanding of the processes underlying mitochondrial failure may lead to urgently needed treatment innovations. It considers individual mitochondrial proteins that have emerged as promising drug targets and evaluates neuroprotective agents that could improve the functional state of mitochondria in the setting of AD. CONCLUSIONS:There is great promise in exploring original approaches to preserving mitochondrial viability as a means to achieve breakthroughs in treating AD.

PURPOSE/OBJECTIVE:A device that provides continuous, long-term, accurate seizure detection information to providers and patients could fundamentally alter epilepsy care. Subgaleal (SG) EEG is a promising modality that offers a minimally invasive, safe, and accurate means of long-term seizure monitoring. METHODS:Subgaleal EEG electrodes were placed, at or near the cranial vertex, simultaneously with intracranial EEG electrodes in 21 epilepsy patients undergoing intracranial EEG studies for up to 13 days. A total of 219, 10-minute single-channel SGEEG samples, including 138 interictal awake or sleep segments and 81 seizures (36 temporal lobe, 32 extra-temporal, and 13 simultaneous temporal/extra-emporal onsets) were reviewed by 3 expert readers blinded to the intracranial EEG results, then analyzed for accuracy and interrater reliability. RESULTS:Using a single-channel of SGEEG, reviewers accurately identified 98% of temporal and extratemporal onset, intracranial, EEG-verified seizures with a sensitivity of 98% and specificity of 99%. All focal to bilateral tonic--clonic seizures were correctly identified. CONCLUSIONS:Single-channel SGEEG, placed at or near the vertex, reliably identifies focal and secondarily generalized seizures. These findings demonstrate that the SG space at the cranial vertex may be an appropriate site for long-term ambulatory seizure monitoring.

Background/Significance: Catatonia is common in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (Espinola-Nadurille, 2019). The glutamate NMDAR antagonists amantadine and memantine are effective in catatonia (Beach, 2017), but data on their use in anti-NMDAR encephalitis is limited. We describe three patients with catatonia due to anti-NMDAR encephalitis treated with NMDAR antagonists and propose a possible mechanism underlying differential outcomes. Case 1: A 20-year-old woman presented with catatonic symptoms after successful treatment of anti-NMDAR encephalitis with immunotherapy and salpingo-oopherectomy for ovarian teratoma. Initial Bush-Francis Catatonia Rating Scale (BFCRS) score was 22. Lorazepam 2.5 mg three times daily was partially effective, but increased doses caused sedation. Memantine was titrated to 10 mg twice daily with complete resolution of catatonia over two weeks. Case 2: A 26-year-old woman presented with catatonic with BFCRS score of 25, after successful immunotherapy for anti-NMDAR encephalitis. Lorazepam 2 mg four times daily was partially effective, but further increase caused respiratory depression. Memantine 10 mg daily resulted in further improvement. Lorazepam titration to 4 mg four times daily was then possible, with complete resolution of catatonia over two weeks. Case 3: A 31-year-old woman with anti-NMDAR encephalitis presented with catatonic symptoms with BFCRS score of 22, after a hospital course significant for limited response to immunotherapy with persistently elevated serum anti-NMDAR antibody titers. Lorazepam 2 mg three times daily was partially effective, but further increase caused sedation. Both amantadine 100 mg twice daily and memantine 10 mg were trialed but were discontinued due to agitation. Mutism and negativism persisted, with a discharge BFCRS score of 12.
Discussion(s): Memantine was effective for catatonia and well tolerated in two patients with successfully treated anti-NMDAR encephalitis, but both amantadine and memantine caused agitation in a third patient with active disease. NMDARs are reversibly internalized in the presence of anti-NMDAR antibodies, leading to a compensatory increase in downstream glutamatergic tone. We hypothesize that NMDAR reemergence after successful treatment, in the context of excess extracellular glutamate, creates a state of excitotoxicity contributing to catatonic signs for which NMDAR blockade can be effective. In the third case, where NMDARs presumably remained internalized in the presence of persistent anti-NMDAR antibodies and a state of NMDAR hypofunction persisted, further NMDAR blockade caused clinical worsening. Conclusion/Implications: NMDAR antagonists can be safe and effective in patients with residual catatonia following successful treatment of anti-NMDAR encephalitis but may be less useful during active disease. More work is needed to clarify best practices for patients with catatonia due to anti-NMDAR encephalitis. References: 1. Espinola-Nadurille M, Flores-Rivera J, Rivas-Alonso V, et al. Catatonia in patients with anti-NMDA receptor encephalitis. Psychiatry Clin Neurosci. 2019;73(9):574-580. 2. Beach SR, Gomez-Bernal F, Huffman JC, Fricchione GL. Alternative treatment strategies for catatonia: A systematic review. Gen Hosp Psychiatry. 2017;48(June):1-19.
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Mucopolysaccharidosis (MPS) VII is an ultra-rare, autosomal-recessive, metabolic disease caused by a deficiency of β-glucuronidase, a lysosomal enzyme that hydrolyzes glycosaminoglycans (GAGs), including dermatan sulfate (DS), chondroitin sulfate, and heparan sulfate (HS). β-glucuronidase deficiency leads to progressive accumulation of undegraded GAGs in lysosomes of affected tissues, which may cause hydrops fetalis, short stature, hepatosplenomegaly, and cognitive impairment. An open-label, multicenter, phase II study was conducted in 8 pediatric subjects <5 years of age with MPS VII. Subjects received the recombinant human β-glucuronidase vestronidase alfa 4 mg/kg by intravenous infusion every other week for 48 weeks (treatment period). Those who completed the 48-week treatment were offered to continue treatment with vestronidase alfa 4 mg/kg for up to 240 weeks or until withdrawal of consent, discontinuation, or study termination (continuation period). The level of GAG excreted in urine (uGAG) above normal has been shown to correlate with disease severity and clinical outcomes in MPS diseases. Therefore, the primary efficacy endpoint of this study was to determine the mean percentage change in uGAG DS excretion from baseline to week 48. Statistically significant reductions in uGAG DS from baseline were observed at each visit (p < 0.0001), with a least square mean (standard error) percentage change of -60% (6.6) at week 4 (first post-baseline assessment) and -61% (6.41) at week 48 (final assessment during treatment period). Secondary efficacy endpoints included change from baseline to week 48 in growth and hepatosplenomegaly. Positive trends were observed toward increased standing height Z-score (mean [standard deviation] at baseline, -2.630 [1.17], n = 8; at week 48, -2.045 [0.27], n = 7) and growth velocity (mean [SD] Z-score at baseline, -2.59 [1.49], n = 4; at week 48, -0.39 [2.10], n = 4; p = 0.27). Hepatomegaly was resolved in 3 of 3 subjects assessed by ultrasound and in 5 of 6 subjects assessed by physical examination; splenomegaly was resolved in 1 of 3 subjects assessed by ultrasound and in 2 of 2 subjects assessed by physical examination. There were no new safety signals identified during this study. Mild-to-moderate infusion-associated reactions occurred in 4 (50%) subjects. In conclusion, long-term vestronidase alfa treatment demonstrated a rapid and sustained reduction in uGAGs, maintained growth, and improved hepatosplenomegaly in pediatric subjects with MPS VII <5 years of age. Trial registration: NCT02418455.

BACKGROUND:To date, public health policies implemented during the COVID-19 pandemic have been evaluated on the basis of their ability to reduce transmission and minimise economic harm. We aimed to assess the association between COVID-19 policy restrictions and mental health during the COVID-19 pandemic. METHODS:In this longitudinal analysis, we combined daily policy stringency data from the Oxford COVID-19 Government Response Tracker with psychological distress scores and life evaluations captured in the Imperial College London-YouGov COVID-19 Behaviour Tracker Global Survey in fortnightly cross-sections from samples of 15 countries between April 27, 2020, and June 28, 2021. The mental health questions provided a sample size of 432 642 valid responses, with an average of 14 918 responses every 2 weeks. To investigate how policy stringency was associated with mental health, we considered two potential mediators: observed physical distancing and perceptions of the government's handling of the pandemic. Countries were grouped on the basis of their response to the COVID-19 pandemic as those pursuing an elimination strategy (countries that aimed to eliminate community transmission of SARS-CoV-2 within their borders) or those pursuing a mitigation strategy (countries that aimed to control SARS-CoV-2 transmission). Using a combined dataset of country-level and individual-level data, we estimated linear regression models with country-fixed effects (ie, dummy variables representing the countries in our sample) and with individual and contextual covariates. Additionally, we analysed data from a sample of Nordic countries, to compare Sweden (that pursued a mitigation strategy) to other Nordic countries (that adopted a near-elimination strategy). FINDINGS/RESULTS:Controlling for individual and contextual variables, higher policy stringency was associated with higher mean psychological distress scores and lower life evaluations (standardised coefficients β=0·014 [95% CI 0·005 to 0·023] for psychological distress; β=-0·010 [-0·015 to -0·004] for life evaluation). Pandemic intensity (number of deaths per 100 000 inhabitants) was also associated with higher mean psychological distress scores and lower life evaluations (standardised coefficients β=0·016 [0·008 to 0·025] for psychological distress; β=-0·010 [-0·017 to -0·004] for life evaluation). The negative association between policy stringency and mental health was mediated by observed physical distancing and perceptions of the government's handling of the pandemic. We observed that countries pursuing an elimination strategy used different policy timings and intensities compared with countries pursuing a mitigation strategy. The containment policies of countries pursuing elimination strategies were on average less stringent, and fewer deaths were observed. INTERPRETATION/CONCLUSIONS:Changes in mental health measures during the first 15 months of the COVID-19 pandemic were small. More stringent COVID-19 policies were associated with poorer mental health. Elimination strategies minimised transmission and deaths, while restricting mental health effects. FUNDING/BACKGROUND:None.

INTRODUCTION/BACKGROUND:We conducted a systematic review and meta-analysis of the cognitive effects of coronavirus disease 2019 (COVID-19) in adults with no prior history of cognitive impairment. METHODS:Searches in Medline/Web of Science/Embase from January 1, 2020, to December 13, 2021, were performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.  A meta-analysis of the Montreal Cognitive Assessment (MoCA) total score comparing recovered COVID-19 and healthy controls was performed. RESULTS:Oof 6202 articles, 27 studies with 2049 individuals were included (mean age = 56.05 years, evaluation time ranged from the acute phase to 7 months post-infection). Impairment in executive functions, attention, and memory were found in post-COVID-19 patients.  The meta-analysis was performed with a subgroup of 290 individuals and showed a difference in MoCA score between post-COVID-19 patients versus controls (mean difference = -0.94, 95% confidence interval [CI] -1.59, -0.29; P = .0049). DISCUSSION/CONCLUSIONS:Patients recovered from COVID-19 have lower general cognition compared to healthy controls up to 7 months post-infection.

BACKGROUND:CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy. METHODS:In the double-blind phase of this randomised, placebo-controlled, phase 3 trial, done at 39 outpatient clinics in eight countries (Australia, France, Israel, Italy, Poland, Russia, the UK, and the USA), patients were eligible if they were aged 2-21 years with a pathogenic or probably pathogenic CDKL5 variant and at least 16 major motor seizures (defined as bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic) per 28 days in each 4-week period of an 8-week historical period. After a 6-week prospective baseline period, patients were randomly assigned (1:1) via an interactive web response system to receive either enteral adjunctive ganaxolone or matching enteral adjunctive placebo (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing >28 kg) for 17 weeks. Patients, caregivers, investigators (including those analysing data), trial staff, and the sponsor (other than the investigational product manager) were masked to treatment allocation. The primary efficacy endpoint was percentage change in median 28-day major motor seizure frequency from the baseline period to the 17-week double-blind phase and was analysed (using a Wilcoxon-rank sum test) in all patients who received at least one dose of trial treatment and for whom baseline data were available. Safety (compared descriptively across groups) was analysed in all patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT03572933, and the open-label extension phase is ongoing. FINDINGS/RESULTS:Between June 25, 2018, and July 2, 2020, 114 patients were screened for eligibility, of whom 101 (median age 6 years [IQR 3 to 10]) were randomly assigned to receive either ganaxolone (n=50) or placebo (n=51). All patients received at least one dose of a study drug, but seizure frequency for one patient in the ganaxolone group was not recorded at baseline and so the primary endpoint was analysed in a population of 100 patients. There was a median percentage change in 28-day major motor seizure frequency of -30·7% (IQR -49·5 to -1·9) in the ganaxolone group and of -6·9% (-24·1 to 39·7) in the placebo group (p=0·0036). The Hodges-Lehmann estimate of median difference in responses to ganaxolone versus placebo was -27·1% (95% CI -47·9 to - 9·6). Treatment-emergent adverse events occurred in 43 (86%) of 50 patients in the ganaxolone group and in 45 (88%) of 51 patients in the placebo group. Somnolence, pyrexia, and upper respiratory tract infections occurred in at least 10% of patients in the ganaxolone group and more frequently than in the placebo group. Serious adverse events occurred in six (12%) patients in the ganaxolone group and in five (10%) patients in the placebo group. Two (4%) patients in the ganaxolone group and four (8%) patients in the placebo group discontinued the trial. There were no deaths in the double-blind phase. INTERPRETATION/CONCLUSIONS:Ganaxolone significantly reduced the frequency of CDD-associated seizures compared with placebo and was generally well tolerated. Results from what is, to our knowledge, the first controlled trial in CDD suggest a potential treatment benefit for ganaxolone. Long-term treatment is being assessed in the ongoing open-label extension phase of this trial. FUNDING/BACKGROUND:Marinus Pharmaceuticals.

Fulminant IIH in pregnancy requires multidisciplinary collaboration and immediate CSF diversion.

OBJECTIVE:The main goal of this study was to explore the latent structure and genetic basis of cognitive processes involved in the Wisconsin Card Sorting Task (WCST) within phenotypic, behavioral genetic, and molecular genetic research paradigms. METHOD/METHODS:The sample used in phenotypic and behavioral genetic analyses comprised 468 twins (154 monozygotic and 80 dizygotic twin pairs), while molecular genetic analyses were performed on 404 twins from the same sample. The zygosity of most twin pairs (96.8%) was determined via deoxyribonucleic acid (DNA) analysis of buccal swabs. Trained researchers administered the Wisconsin Card Sorting Test (WCST; Heaton et al., 1993) to the entire sample. RESULTS:Met- genotype. CONCLUSIONS:Met + genotype showed significant main effects on different WCST measures. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

OBJECTIVE:We examined the prevalence of risky alcohol and cannabis use among Brazilian varsity college athletes and whether this group had a greater likelihood of risky use than non-athletes. METHODS:In 2009, Brazilian college students (n=12,711) were recruited for a national stratified random survey. Their sociodemographic characteristics, mental health, substance use, and participation in varsity sports were assessed. Binary logistic regression models were used to examine the association between varsity athlete status and moderate to high-risk alcohol and cannabis use. RESULTS:Among varsity athletes, 67.6 and 10.7% reported risky alcohol and cannabis use, respectively. Varsity athletes had greater odds of risky alcohol consumption than non-athletes (aOR = 2.02, 95%CI 1.08-3.78). Varsity athletes also had greater odds of risky cannabis use than non-athletes in unadjusted analyses (OR = 2.57, 95%CI 1.05-6.28), although this relationship was attenuated after covariate adjustment. CONCLUSIONS:Among college students in Brazil, varsity athletes had a higher prevalence of risky alcohol and cannabis use than non-athletes. The rates were considerably higher than those observed among samples of U.S. college athletes. Future research should examine the use of these substances among varsity college athletes in other middle-income countries since these findings will likely guide prevention and treatment efforts.