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Researching COVID to enhance recovery (RECOVER) tissue pathology study protocol: Rationale, objectives, and design

Troxel, Andrea B; Bind, Marie-Abele C; Flotte, Thomas J; Cordon-Cardo, Carlos; Decker, Lauren A; Finn, Aloke V; Padera, Robert F; Reichard, R Ross; Stone, James R; Adolphi, Natalie L; Casimero, Faye Victoria C; Crary, John F; Elifritz, Jamie; Faustin, Arline; Ghosh, Saikat Kumar B; Krausert, Amanda; Martinez-Lage, Maria; Melamed, Jonathan; Mitchell, Roger A; Sampson, Barbara A; Seifert, Alan C; Simsir, Aylin; Adams, Cheryle; Haasnoot, Stephanie; Hafner, Stephanie; Siciliano, Michelle A; Vallejos, Brittany B; Del Boccio, Phoebe; Lamendola-Essel, Michelle F; Young, Chloe E; Kewlani, Deepshikha; Akinbo, Precious A; Parent, Brendan; Chung, Alicia; Cato, Teresa C; Mudumbi, Praveen C; Esquenazi-Karonika, Shari; Wood, Marion J; Chan, James; Monteiro, Jonathan; Shinnick, Daniel J; Thaweethai, Tanayott; Nguyen, Amber N; Fitzgerald, Megan L; Perlowski, Alice A; Stiles, Lauren E; Paskett, Moira L; Katz, Stuart D; Foulkes, Andrea S; ,
IMPORTANCE/OBJECTIVE:SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) tissue pathology study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository. METHODS:RECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Causal inference methods will be employed to investigate associations between risk factors and pathologic outcomes. DISCUSSION/CONCLUSIONS:RECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC.
PMID: 38198481
ISSN: 1932-6203
CID: 5628642

Localized proteomic differences in the choroid plexus of Alzheimer's disease and epilepsy patients

Leitner, Dominique F.; Kanshin, Evgeny; Faustin, Arline; Thierry, Manon; Friedman, Daniel; Devore, Sasha; Ueberheide, Beatrix; Devinsky, Orrin; Wisniewski, Thomas
Introduction: Alzheimer's disease (AD) and epilepsy are reciprocally related. Among sporadic AD patients, clinical seizures occur in 10"“22% and subclinical epileptiform abnormalities occur in 22"“54%. Cognitive deficits, especially short-term memory impairments, occur in most epilepsy patients. Common neurophysiological and molecular mechanisms occur in AD and epilepsy. The choroid plexus undergoes pathological changes in aging, AD, and epilepsy, including decreased CSF turnover, amyloid beta (Aβ), and tau accumulation due to impaired clearance and disrupted CSF amino acid homeostasis. This pathology may contribute to synaptic dysfunction in AD and epilepsy. Methods: We evaluated control (n = 8), severe AD (n = 8; A3, B3, C3 neuropathology), and epilepsy autopsy cases (n = 12) using laser capture microdissection (LCM) followed by label-free quantitative mass spectrometry on the choroid plexus adjacent to the hippocampus at the lateral geniculate nucleus level. Results: Proteomics identified 2,459 proteins in the choroid plexus. At a 5% false discovery rate (FDR), 616 proteins were differentially expressed in AD vs. control, 1 protein in epilepsy vs. control, and 438 proteins in AD vs. epilepsy. There was more variability in the epilepsy group across syndromes. The top 20 signaling pathways associated with differentially expressed proteins in AD vs. control included cell metabolism pathways; activated fatty acid beta-oxidation (p = 2.00 x 10−7, z = 3.00), and inhibited glycolysis (p = 1.00 x 10−12, z = −3.46). For AD vs. epilepsy, the altered pathways included cell metabolism pathways, activated complement system (p = 5.62 x 10−5, z = 2.00), and pathogen-induced cytokine storm (p = 2.19 x 10−2, z = 3.61). Of the 617 altered proteins in AD and epilepsy vs. controls, 497 (81%) were positively correlated (p < 0.0001, R2 = 0.27). Discussion: We found altered signaling pathways in the choroid plexus of severe AD cases and many correlated changes in the protein expression of cell metabolism pathways in AD and epilepsy cases. The shared molecular mechanisms should be investigated further to distinguish primary pathogenic changes from the secondary ones. These mechanisms could inform novel therapeutic strategies to prevent disease progression or restore normal function. A focus on dual-diagnosed AD/epilepsy cases, specific epilepsy syndromes, such as temporal lobe epilepsy, and changes across different severity levels in AD and epilepsy would add to our understanding.
ISSN: 1664-2295
CID: 5619802

Reasearching COVID to enhance recorvery (RECOVER) autopsy tissue pathology study protocol: Rationale, objectives, and design [PrePrint]

Troxel, Andrea B; Bind, Marie-Abele C; Flotte, Thomas J; Cordon-Cardo, Carlos; Decker, Lauren A; Finn, Aloke V; Padera, Robert F; Reichard, R. Ross; Stone, James R; Adolphi, Natalie L; Casimero, Faye; Crary, John F; Elifritz, Jamie; Faustin, Arline; Kumar B Ghosh, Saikat; Krausert, Amanda; Martinez-Lage, Maria; Melamed, Jonathan; Mitchell Jr, Roger A; Sampson, Barbara A; Seifert, Alan C; Simsir, Aylin; Adams, Cheryle; Haasnoot, Stephanie; Hafner, Stephanie; Siciliano, Michelle A; Vallejos, Britanny B; Del Boccio, Pheobe; Lamendola-Essel; Michelle F; Young, Chloe E; Kewlani, Deepshikha; Akinbo, Precious A; Parent, Brendan; Chung, Alicia; Cato, Teresa C; Mudumbi, Praveen; Esquenazi-Karonika, Shari; Wood, Marion J; Chan, James; Monteiro, Jonathan; Shinnick, Daniel J; Thaweethai, Tanayott; Nguyen, Amber N; Fitzgerald, Megan L; Perlowski, Alice A; Stiles, Lauren E; Paskett, Moira L, Katz, Stuart D; Foulkes, Andrea S
ISSN: n/a
CID: 5573572

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors-A prospective study and guidelines for clinical testing

Galbraith, Kristyn; Vasudevaraja, Varshini; Serrano, Jonathan; Shen, Guomiao; Tran, Ivy; Abdallat, Nancy; Wen, Mandisa; Patel, Seema; Movahed-Ezazi, Misha; Faustin, Arline; Spino-Keeton, Marissa; Roberts, Leah Geiser; Maloku, Ekrem; Drexler, Steven A; Liechty, Benjamin L; Pisapia, David; Krasnozhen-Ratush, Olga; Rosenblum, Marc; Shroff, Seema; Boué, Daniel R; Davidson, Christian; Mao, Qinwen; Suchi, Mariko; North, Paula; Hopp, Amanda; Segura, Annette; Jarzembowski, Jason A; Parsons, Lauren; Johnson, Mahlon D; Mobley, Bret; Samore, Wesley; McGuone, Declan; Gopal, Pallavi P; Canoll, Peter D; Horbinski, Craig; Fullmer, Joseph M; Farooqui, Midhat S; Gokden, Murat; Wadhwani, Nitin R; Richardson, Timothy E; Umphlett, Melissa; Tsankova, Nadejda M; DeWitt, John C; Sen, Chandra; Placantonakis, Dimitris G; Pacione, Donato; Wisoff, Jeffrey H; Teresa Hidalgo, Eveline; Harter, David; William, Christopher M; Cordova, Christine; Kurz, Sylvia C; Barbaro, Marissa; Orringer, Daniel A; Karajannis, Matthias A; Sulman, Erik P; Gardner, Sharon L; Zagzag, David; Tsirigos, Aristotelis; Allen, Jeffrey C; Golfinos, John G; Snuderl, Matija
BACKGROUND/UNASSIGNED:Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. METHODS/UNASSIGNED:We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. RESULTS/UNASSIGNED:Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. CONCLUSIONS/UNASSIGNED:DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.
PMID: 37476329
ISSN: 2632-2498
CID: 5536102

Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer's disease

Sadick, Jessica S; O'Dea, Michael R; Hasel, Philip; Dykstra, Taitea; Faustin, Arline; Liddelow, Shane A
Resolving glial contributions to Alzheimer's disease (AD) is necessary because changes in neuronal function, such as reduced synaptic density, altered electrophysiological properties, and degeneration, are not entirely cell autonomous. To improve understanding of transcriptomic heterogeneity in glia during AD, we used single-nuclei RNA sequencing (snRNA-seq) to characterize astrocytes and oligodendrocytes from apolipoprotein (APOE) Ɛ2/3 human AD and age- and genotype-matched non-symptomatic (NS) brains. We enriched astrocytes before sequencing and characterized pathology from the same location as the sequenced material. We characterized baseline heterogeneity in both astrocytes and oligodendrocytes and identified global and subtype-specific transcriptomic changes between AD and NS astrocytes and oligodendrocytes. We also took advantage of recent human and mouse spatial transcriptomics resources to localize heterogeneous astrocyte subtypes to specific regions in the healthy and inflamed brain. Finally, we integrated our data with published AD snRNA-seq datasets, highlighting the power of combining datasets to resolve previously unidentifiable astrocyte subpopulations.
PMID: 35381189
ISSN: 1097-4199
CID: 5204852

Proteomic differences in hippocampus and cortex of sudden unexplained death in childhood

Leitner, Dominique F; William, Christopher; Faustin, Arline; Askenazi, Manor; Kanshin, Evgeny; Snuderl, Matija; McGuone, Declan; Wisniewski, Thomas; Ueberheide, Beatrix; Gould, Laura; Devinsky, Orrin
Sudden unexplained death in childhood (SUDC) is death of a child over 1 year of age that is unexplained after review of clinical history, circumstances of death, and complete autopsy with ancillary testing. Multiple etiologies may cause SUDC. SUDC and sudden unexpected death in epilepsy (SUDEP) share clinical and pathological features, suggesting some similarities in mechanism of death and possible abnormalities in hippocampus and cortex. To identify molecular signaling pathways, we performed label-free quantitative mass spectrometry on microdissected frontal cortex, hippocampal dentate gyrus (DG), and cornu ammonis (CA1-3) in SUDC (n = 19) and pediatric control cases (n = 19) with an explained cause of death. At a 5% false discovery rate (FDR), we found differential expression of 660 proteins in frontal cortex, 170 in DG, and 57 in CA1-3. Pathway analysis of altered proteins identified top signaling pathways associated with activated oxidative phosphorylation (p = 6.3 × 10-15, z = 4.08) and inhibited EIF2 signaling (p = 2.0 × 10-21, z = - 2.56) in frontal cortex, and activated acute phase response in DG (p = 8.5 × 10-6, z = 2.65) and CA1-3 (p = 4.7 × 10-6, z = 2.00). Weighted gene correlation network analysis (WGCNA) of clinical history indicated that SUDC-positive post-mortem virology (n = 4/17) had the most significant module in each brain region, with the top most significant associated with decreased mRNA metabolic processes (p = 2.8 × 10-5) in frontal cortex. Additional modules were associated with clinical history, including fever within 24 h of death (top: increased mitochondrial fission in DG, p = 1.8 × 10-3) and febrile seizure history (top: decreased small molecule metabolic processes in frontal cortex, p = 8.8 × 10-5) in all brain regions, neuropathological hippocampal findings in the DG (top: decreased focal adhesion, p = 1.9 × 10-3). Overall, cortical and hippocampal protein changes were present in SUDC cases and some correlated with clinical features. Our studies support that proteomic studies of SUDC cohorts can advance our understanding of the pathogenesis of these tragedies and may inform the development of preventive strategies.
PMID: 35333953
ISSN: 1432-0533
CID: 5200692

The amyloid plaque proteome in early onset Alzheimer's disease and Down syndrome

Drummond, Eleanor; Kavanagh, Tomas; Pires, Geoffrey; Marta-Ariza, Mitchell; Kanshin, Evgeny; Nayak, Shruti; Faustin, Arline; Berdah, Valentin; Ueberheide, Beatrix; Wisniewski, Thomas
Amyloid plaques contain many proteins in addition to beta amyloid (Aβ). Previous studies examining plaque-associated proteins have shown these additional proteins are important; they provide insight into the factors that drive amyloid plaque development and are potential biomarkers or therapeutic targets for Alzheimer's disease (AD). The aim of this study was to comprehensively identify proteins that are enriched in amyloid plaques using unbiased proteomics in two subtypes of early onset AD: sporadic early onset AD (EOAD) and Down Syndrome (DS) with AD. We focused our study on early onset AD as the drivers of the more aggressive pathology development in these cases is unknown and it is unclear whether amyloid-plaque enriched proteins differ between subtypes of early onset AD. Amyloid plaques and neighbouring non-plaque tissue were microdissected from human brain sections using laser capture microdissection and label-free LC-MS was used to quantify the proteins present. 48 proteins were consistently enriched in amyloid plaques in EOAD and DS. Many of these proteins were more significantly enriched in amyloid plaques than Aβ. The most enriched proteins in amyloid plaques in both EOAD and DS were: COL25A1, SMOC1, MDK, NTN1, OLFML3 and HTRA1. Endosomal/lysosomal proteins were particularly highly enriched in amyloid plaques. Fluorescent immunohistochemistry was used to validate the enrichment of four proteins in amyloid plaques (moesin, ezrin, ARL8B and SMOC1) and to compare the amount of total Aβ, Aβ40, Aβ42, phosphorylated Aβ, pyroglutamate Aβ species and oligomeric species in EOAD and DS. These studies showed that phosphorylated Aβ, pyroglutamate Aβ species and SMOC1 were significantly higher in DS plaques, while oligomers were significantly higher in EOAD. Overall, we observed that amyloid plaques in EOAD and DS largely contained the same proteins, however the amount of enrichment of some proteins was different in EOAD and DS. Our study highlights the significant enrichment of many proteins in amyloid plaques, many of which may be potential therapeutic targets and/or biomarkers for AD.
PMID: 35418158
ISSN: 2051-5960
CID: 5201962

Blinded Review of Hippocampal Neuropathology in Sudden Unexplained Death in Childhood Reveals Inconsistent Observations and Similarities to Explained Pediatric Deaths

Leitner, Dominique F; McGuone, Declan; William, Christopher; Faustin, Arline; Askenazi, Manor; Snuderl, Matija; Guzzetta, Melissa; Jarrell, Heather S; Maloney, Katherine; Reichard, Ross; Smith, Colin; Weedn, Victor; Wisniewski, Thomas; Gould, Laura; Devinsky, Orrin
AIMS/OBJECTIVE:Hippocampal findings are implicated in the pathogenesis of sudden unexplained death in childhood (SUDC), although some studies have identified similar findings in sudden explained death in childhood (SEDC) cases. We blindly reviewed hippocampal histology in SUDC and SEDC controls. METHODS:Hippocampal H&E slides (n=67; 36 SUDC, 31 controls) from clinical and forensic collaborators were evaluated by 9 blinded reviewers: 3 board-certified forensic pathologists, 3 neuropathologists, and 3 dual-certified neuropathologist/forensic pathologists. RESULTS:Among nine reviewers, about 50% of hippocampal sections were rated as abnormal (SUDC 52.5%, controls 53.0%), with no difference by cause of death (COD) (p=0.16) or febrile seizure history (p=0.90). There was little agreement among nine reviewers on whether a slide was within normal range (Fleiss' kappa=0.014, p=0.47). Within reviewer groups, there were no findings more frequent in SUDC compared to controls, with variability in pyramidal neuron and dentate gyrus findings. Across reviewer groups, there was concordance for bilamination and granule cell loss. Neither SUDC (51.2%) nor control (55.9%) slides were considered contributory to determining COD (p=0.41). CONCLUSIONS:The lack of an association of hippocampal findings in SUDC and controls, as well as inconsistency of observations by multiple blinded reviewers, indicates discrepancy with previous studies and an inability to reliably identify hippocampal malformation associated with sudden death (HMASD). These findings underscore a need for larger studies to standardize evaluation of hippocampal findings, identify the range of normal variation and, changes unrelated to SUDC or febrile seizures. Molecular studies may help identify novel immunohistological markers that inform on COD.
PMID: 34164845
ISSN: 1365-2990
CID: 4918622

Raphe and ventrolateral medulla proteomics in epilepsy and sudden unexpected death in epilepsy

Leitner, Dominique F; Kanshin, Evgeny; Askenazi, Manor; Faustin, Arline; Friedman, Daniel; Devore, Sasha; Ueberheide, Beatrix; Wisniewski, Thomas; Devinsky, Orrin
Brainstem nuclei dysfunction is implicated in sudden unexpected death in epilepsy. In animal models, deficient serotonergic activity is associated with seizure-induced respiratory arrest. In humans, glia are decreased in the ventrolateral medullary pre-Botzinger complex that modulate respiratory rhythm, as well as in the medial medullary raphe that modulate respiration and arousal. Finally, sudden unexpected death in epilepsy cases have decreased midbrain volume. To understand the potential role of brainstem nuclei in sudden unexpected death in epilepsy, we evaluated molecular signalling pathways using localized proteomics in microdissected midbrain dorsal raphe and medial medullary raphe serotonergic nuclei, as well as the ventrolateral medulla in brain tissue from epilepsy patients who died of sudden unexpected death in epilepsy and other causes in diverse epilepsy syndromes and non-epilepsy control cases (n = 15-16 cases per group/region). Compared with the dorsal raphe of non-epilepsy controls, we identified 89 proteins in non-sudden unexpected death in epilepsy and 219 proteins in sudden unexpected death in epilepsy that were differentially expressed. These proteins were associated with inhibition of EIF2 signalling (P-value of overlap = 1.29 × 10-8, z = -2.00) in non-sudden unexpected death in epilepsy. In sudden unexpected death in epilepsy, there were 10 activated pathways (top pathway: gluconeogenesis I, P-value of overlap = 3.02 × 10-6, z = 2.24) and 1 inhibited pathway (fatty acid beta-oxidation, P-value of overlap = 2.69 × 10-4, z = -2.00). Comparing sudden unexpected death in epilepsy and non-sudden unexpected death in epilepsy, 10 proteins were differentially expressed, but there were no associated signalling pathways. In both medullary regions, few proteins showed significant differences in pairwise comparisons. We identified altered proteins in the raphe and ventrolateral medulla of epilepsy patients, including some differentially expressed in sudden unexpected death in epilepsy cases. Altered signalling pathways in the dorsal raphe of sudden unexpected death in epilepsy indicate a shift in cellular energy production and activation of G-protein signalling, inflammatory response, stress response and neuronal migration/outgrowth. Future studies should assess the brain proteome in relation to additional clinical variables (e.g. recent tonic-clonic seizures) and in more of the reciprocally connected cortical and subcortical regions to better understand the pathophysiology of epilepsy and sudden unexpected death in epilepsy.
PMID: 35928051
ISSN: 2632-1297
CID: 5288272

Plasma biomarkers of neurodegeneration and neuroinflammation in hospitalized COVID-19 patients with and without new neurological symptom

Boutajangout, Allal; Frontera, Jennifer; Debure, Ludovic; Vedvyas, Alok; Faustin, Arline; Wisniewski, Thomas
ISSN: 1552-5279
CID: 5297192