Faculty Bibliography

Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer's diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer's pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET were included from ADNI. Cross-sectional relationships of plasma p-tau181 with PET biomarkers were tested. Longitudinally, we further investigated whether different p-tau181 levels at baseline predicted different progression of Alzheimer's pathological changes in the brain. We found plasma p-tau181 significantly correlated with brain amyloid (Spearman ρ = 0.45, P < 0.0001), tau (0.25, P = 0.0003), and FDG PET uptakes (-0.37, P < 0.0001), and increased along the Alzheimer's continuum. Individually, plasma p-tau181 could detect abnormal amyloid, tau pathologies and hypometabolism in the brain, similar with or even better than clinical indicators. The diagnostic accuracy of plasma p-tau181 elevated significantly when combined with clinical information (AUC = 0.814 for amyloid PET, 0.773 for tau PET, and 0.708 for FDG PET). Relationships of plasma p-tau181 with brain pathologies were partly or entirely mediated by the corresponding CSF biomarkers. Besides, individuals with abnormal plasma p-tau181 level (>18.85 pg/ml) at baseline had a higher risk of pathological progression in brain amyloid (HR: 2.32, 95%CI 1.32-4.08) and FDG PET (3.21, 95%CI 2.06-5.01) status. Plasma p-tau181 may be a sensitive screening test for detecting brain pathologies, and serve as a predictive biomarker for Alzheimer's pathophysiology.

A biological research framework to define Alzheimer' disease with dichotomized biomarker measurement was proposed by National Institute on Aging-Alzheimer's Association (NIA-AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic ¹⁸F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline ¹⁸F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal β-amyloid in neocortical regions but prompt cognitive decline by interacting with β-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer's disease could be illustrated with biomarker measurement under NIA-AA framework. Clinical-neuroimaging-neuropathological studies in other cohorts are needed to validate these findings.

Neuroinflammation is associated with Alzheimer's disease, but the application of cerebrospinal fluid measures of inflammatory proteins may be limited by overlapping pathways and relationships between them. In this work, we measure 15 cerebrospinal proteins related to microglial and T-cell functions, and show them to reproducibly form functionally-related groups within and across diagnostic categories in 382 participants from the Alzheimer's Disease Neuro-imaging Initiative as well participants from two independent cohorts. We further show higher levels of proteins related to soluble tumor necrosis factor receptor 1 are associated with reduced risk of conversion to dementia in the multi-centered (p = 0.027) and independent (p = 0.038) cohorts of people with mild cognitive impairment due to predicted Alzheimer's disease, while higher soluble TREM2 levels associated with slower decline in the dementia stage of Alzheimer's disease. These inflammatory proteins thus provide prognostic information independent of established Alzheimer's markers.

Brain arteriovenous malformations (bAVMs) are relatively rare, although their potential for secondary intracranial haemorrhage (ICH) makes their diagnosis and management essential to the community. Currently, invasive therapies (surgical resection, stereotactic radiosurgery and endovascular embolisation) are the only interventions that offer a reduction in ICH risk. There is no designated medical therapy for bAVM, although there is growing animal and human evidence supporting a role for bevacizumab to reduce the size of AVMs. In this single-arm pilot study, two patients with large bAVMs (deemed unresectable by an interdisciplinary team) received bevacizumab 5 mg/kg every 2 weeks for 12 weeks. Due to limitations of external funding, the intended sample size of 10 participants was not reached. Primary outcome measure was change in bAVM volume from baseline at 26 and 52 weeks. No change in bAVM volume was observed 26 or 52 weeks after bevacizumab treatment. No clinically important adverse events were observed during the 52-week study period. There were no observed instances of ICH. Sera vascular endothelial growth factor levels were reduced at 26 weeks and returned to baseline at 52 weeks. This pilot study is the first to test bevacizumab for patients with bAVMs. Bevacizumab therapy was well tolerated in both subjects. No radiographic changes were observed over the 52-week study period. Subsequent larger clinical trials are in order to assess for dose-dependent efficacy and rarer adverse drug effects. Trial registration number: NCT02314377.

Neurological complications worsen outcomes in COVID-19. To define the prevalence of neurological conditions among hospitalized patients with a positive SARS-CoV-2 reverse transcription polymerase chain reaction test in geographically diverse multinational populations during early pandemic, we used electronic health records (EHR) from 338 participating hospitals across 6 countries and 3 continents (January-September 2020) for a cross-sectional analysis. We assessed the frequency of International Classification of Disease code of neurological conditions by countries, healthcare systems, time before and after admission for COVID-19 and COVID-19 severity. Among 35,177 hospitalized patients with SARS-CoV-2 infection, there was an increase in the proportion with disorders of consciousness (5.8%, 95% confidence interval [CI] 3.7-7.8%, p_FDR < 0.001) and unspecified disorders of the brain (8.1%, 5.7-10.5%, p_FDR < 0.001) when compared to the pre-admission proportion. During hospitalization, the relative risk of disorders of consciousness (22%, 19-25%), cerebrovascular diseases (24%, 13-35%), nontraumatic intracranial hemorrhage (34%, 20-50%), encephalitis and/or myelitis (37%, 17-60%) and myopathy (72%, 67-77%) were higher for patients with severe COVID-19 when compared to those who never experienced severe COVID-19. Leveraging a multinational network to capture standardized EHR data, we highlighted the increased prevalence of central and peripheral neurological phenotypes in patients hospitalized with COVID-19, particularly among those with severe disease.

Fast and slow progressor phenotypes of infarct growth due to anterior circulation large vessel occlusion (ACLVO) remain poorly understood. We aimed to define clinical predictors of fast and slow progressors in a retrospective study of patients with ACLVO who underwent baseline advanced imaging within 24 hours of stroke onset. Fast progressors (ischemic core > 70 ml, < 6 hours after onset) and slow progressors (ischemic core ≤ 30 ml, 6 to 24 hours after onset) were identified amongst 185 patients. Clinical and laboratory variables were tested for association with fast or slow progressor status. In the early epoch, no significant differences were found between fast progressors and controls. In the delayed epoch, slow progressors had a median NIHSS of 14 versus 20 (p < 0.01) and MCA occlusion in 80% versus 63% (p < 0.05) relative to controls. In multivariate analyses, NIHSS (OR 0.83, 95% CI 0.73-0.95), hyperlipidemia (OR 4.24, 95% CI 1.01 - 19.3) and hemoglobin concentration (OR 0.75, 95% CI 0.57 - 0.99) were independently associated with slow progressor status. This study indicates that lower initial stroke symptom severity, a history of hyperlipidemia and mild anemia are associated with individual tolerance to ACLVO stroke.

OBJECTIVE:Palatable food (PF) intake is significantly greater in females than males and increases during adolescence. Previous data suggest that puberty and ovarian hormones may contribute to these sex and developmental differences, but few studies have examined this possibility. The aim of the current study was to address these gaps by examining trajectories of PF and chow intake during pre-puberty, puberty, and adulthood in intact female rats (Study 1) as well as in those receiving pre-pubertal ovariectomies (P-OVX) (Study 2). METHOD:We examined our study aims using archival data from 66 intact Sprague-Dawley female rats (Study 1) and 77 P-OVX and 79 intact Sprague-Dawley female rats (Study 2). PF and chow intake were measured using a free-choice, intermittent exposure paradigm in which rats were exposed to both food types starting in pre-puberty and continuing into adulthood. RESULTS:Mixed linear models revealed a specific effect of puberty on PF intake in both studies. PF intake increased substantially during puberty in all rats, but increases were particularly pronounced in P-OVX rats in Study 2. By contrast, chow intake increased significantly during pre-puberty (rather than puberty) in both studies, and these increases were relatively unaffected by P-OVX. DISCUSSION:Findings confirm a specific effect of puberty and ovarian hormone removal on PF intake in female rats. Differential trajectories of PF versus chow intake highlight potential reward-based processes in pubertal and ovarian hormone effects on PF intake in females.

OBJECTIVE:To study if limited frontotemporal electroencephalogram (EEG) can guide sedation changes in highly infectious novel coronavirus disease 2019 (COVID-19) patients receiving neuromuscular blocking agent. METHODS:98 days of continuous frontotemporal EEG from 11 consecutive patients was evaluated daily by an epileptologist to recommend reduction or maintenance of the sedative level. We evaluated the need to increase sedation in the 6 h following this recommendation. Post-hoc analysis of the quantitative EEG was correlated with the level of sedation using a machine learning algorithm. RESULTS:Eleven patients were studied for a total of ninety-eight sedation days. EEG was consistent with excessive sedation on 57 (58%) and adequate sedation on 41 days (42%). Recommendations were followed by the team on 59% (N = 58; 19 to reduce and 39 to keep the sedation level). In the 6 h following reduction in sedation, increases of sedation were needed in 7 (12%). Automatized classification of EEG sedation levels reached 80% (±17%) accuracy. CONCLUSIONS:Visual inspection of a limited EEG helped sedation depth guidance. In a secondary analysis, our data supported that this determination may be automated using quantitative EEG analysis. SIGNIFICANCE:Our results support the use of frontotemporal EEG for guiding sedation in patients with COVID-19.

Critical illness and sepsis are commonly associated with subclinical seizures. COVID-19 frequently causes severe critical illness, but the incidence of electrographic seizures in patients with COVID-19 has been reported to be low. This retrospective case series assessed the incidence of and risks for electrographic seizures in patients hospitalized with COVID-19 who underwent continuous video electroencephalography monitoring (cvEEG) between March 1st, 2020 and June 30th, 2020. One hundred and twenty-two patients were initially identified who resulted SARS-CoV-2 nasopharyngeal RT-PCR swab positivity with any electroencephalography order placed in the EMR. Seventy-nine patients met study inclusion criteria: age ≥18 years, >1 h of cvEEG monitoring, and positive SARS-CoV-2 nasopharyngeal swab PCR. Six (8%) of the 79 patients suffered electrographic seizures (ES), three of whom suffered non-convulsive status epilepticus. Acute hyperkinetic movements were the most common reason for cvEEG in patients with ES (84%). None of the patients undergoing cvEEG for persistent coma (29% of all patients) had ES. Focal slowing (67 vs. 10%), sporadic interictal epileptiform discharges (EDs; 33 vs. 6%), and periodic/rhythmic EDs (67 vs. 1%) were proportionally more frequent among patients with electrographic seizures than those without these seizures. While 15% of patients without ES had generalized periodic discharges (GPDs) with triphasic morphology on EEG, none of the patients with ES had this pattern. Further study is required to assess the predictive values of these risk factors on electrographic seizure incidence and subsequent outcomes.

SARS-CoV-2 messenger RNA vaccination in healthy individuals generates immune protection against COVID-19. However, little is known about SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed patients. We investigated induction of antigen-specific antibody, B cell and T cell responses longitudinally in patients with multiple sclerosis (MS) on anti-CD20 antibody monotherapy (n = 20) compared with healthy controls (n = 10) after BNT162b2 or mRNA-1273 mRNA vaccination. Treatment with anti-CD20 monoclonal antibody (aCD20) significantly reduced spike-specific and receptor-binding domain (RBD)-specific antibody and memory B cell responses in most patients, an effect ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution. By contrast, all patients with MS treated with aCD20 generated antigen-specific CD4 and CD8 T cell responses after vaccination. Treatment with aCD20 skewed responses, compromising circulating follicular helper T (T_FH) cell responses and augmenting CD8 T cell induction, while preserving type 1 helper T (T_H1) cell priming. Patients with MS treated with aCD20 lacking anti-RBD IgG had the most severe defect in circulating T_FH responses and more robust CD8 T cell responses. These data define the nature of the SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients and provide insights into coordinated mRNA vaccine-induced immune responses in humans. Our findings have implications for clinical decision-making and public health policy for immunosuppressed patients including those treated with aCD20.