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OBJECTIVES/HYPOTHESIS - Characterization of the localized adaptive immune response in the airway scar of patients with idiopathic subglottic stenosis (iSGS).
STUDY DESIGN - Basic Science.
METHODS - Utilizing 36 patients with subglottic stenosis (25 idiopathic subglottic stenosis [iSGS], 10 iatrogenic post-intubation stenosis [iLTS], and one granulomatosis with polyangiitis [GPA]) we applied immunohistochemical and immunologic techniques coupled with RNA sequencing.
RESULTS - iSGS, iLTS, and GPA demonstrate a significant immune infiltrate in the subglottic scar consisting of adaptive cell subsets (T cells along with dendritic cells). Interrogation of T cell subtypes showed significantly more CD69 CD103 CD8 tissue resident memory T cells (T ) in the iSGS airway scar than iLTS specimens (iSGS vs. iLTS; 50% vs. 28%, P = .0065). Additionally, subglottic CD8 clones possessed T-cell receptor (TCR) sequences with known antigen specificity for viral and intracellular pathogens.
CONCLUSIONS - The human subglottis is significantly enriched for CD8 tissue resident memory T cells in iSGS, which possess TCR sequences proven to recognize viral and intracellular pathogens. These results inform our understanding of iSGS, provide a direction for future discovery, and demonstrate immunologic function in the human proximal airway. Laryngoscope, 131:610-617, 2021.
© 2020 The American Laryngological, Rhinological and Otological Society, Inc.
Relational memory, or the ability to form contextual associations among items encountered closely in time, is impaired in schizophrenia. The ability to bind items into a relational memory is dependent on the hippocampus, a region that is abnormal in schizophrenia. However, the hippocampus is also involved in exploratory behavior, leaving open the question whether relational memory deficits in schizophrenia are due to failure of relational binding or diminished visual exploration of individual items during encoding. We studied visual exploration patterns during the encoding of face-scene pairs in 66 healthy control subjects and 69 early psychosis patients, to test the hypothesis that differences in visual exploration during the encoding phase can explain task accuracy differences between the two groups. Psychosis patients had lower explicit test accuracy and were less likely to transition from mouth to eyes during encoding. The visual exploration pattern differences between groups did not mediate the relationship between group and explicit test accuracy. We conclude that early psychosis patients have an abnormal pattern of binding items together during encoding that warrants further research.
Copyright © 2020 Elsevier B.V. All rights reserved.
BACKGROUND - Learning and memory are impaired in schizophrenia. Some theories have proposed that one form of memory, habituation, is particularly impaired. Preliminary evidence suggests that memory impairment is associated with failed hippocampal habituation in patients with chronic schizophrenia. We studied how abnormal habituation of the hippocampus is related to relational memory deficits in the early stage of psychosis.
METHODS - We measured hippocampal activity in 62 patients with early psychosis and 70 healthy individuals using functional magnetic resonance imaging. Habituation was defined as the slope of functional magnetic resonance imaging signal change to repeated presentations of faces and objects. Relational memory ability was measured as the slope of preferential viewing during a face-scene pair eye movement task outside the scanner.
RESULTS - Patients with early psychosis showed impaired relational memory (p < .001) and less hippocampal habituation to objects (p = .01) than healthy control subjects. In the healthy control group, better relational memory was associated with faster anterior hippocampal habituation (faces, r = -.28, p = .03). In contrast, patients with early psychosis showed no brain-behavior relationship (r = .12, p = .40).
CONCLUSIONS - We found evidence for disrupted hippocampal habituation in the early stage of psychosis along with an altered association between hippocampal habituation and relational memory ability. These results suggest that neural habituation may provide a novel target for early cognitive interventions in psychosis.
Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Humans constantly take in vast amounts of information, which must be filtered, flexibly manipulated, and integrated into cohesive relational memories in order to choose relevant behaviors. Relational memory is impaired in chronic schizophrenia, which has been linked to hippocampal dysfunction. It is unclear whether relational memory is impaired in the early stage of psychosis.
METHODS - We studied eye movements during a face-scene pairs task as an indirect measure of relational memory in 89 patients in the early stage of psychosis and 84 healthy control participants. During testing, scenes were overlaid with three equally-familiar faces and participants were asked to recall the matching (i.e. previously-paired) face. During Match trials, one face had been previously paired with the scene. During Non-Match trials, no faces matched the scene. Forced-choice explicit recognition was recorded as a direct measure of relational memory.
RESULTS - Healthy control subjects rapidly (within 250-500 ms) showed preferential viewing of the matching face during Match trials. In contrast, preferential viewing was delayed in patients in the early stage of psychosis. Explicit recognition of the matching face was also impaired in the patient group.
CONCLUSIONS - This study provides novel evidence for a relational memory deficit in the early stage of psychosis. Patients showed deficits in both explicit recognition as well as abnormal eye-movement patterns during memory recall. Eye movements provide a promising avenue for the study of relational memory in psychosis, as they allow for the assessment of rapid, nonverbal memory processes.
Copyright © 2019 Elsevier B.V. All rights reserved.
Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4 T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45ROGZMBKi67) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4 and CD8 T cells as culprits of checkpoint inhibitor-associated immune encephalitis.
Working memory (WM) is impaired in psychotic disorders and linked to functional outcome. Most neurobiological models emphasize prefrontal cortex (PFC) dysfunction in the etiology of WM impairment. However, WM is composed of multiple processes, including encoding and maintenance, and the delineation of the neurobiology of these sub-processes has not been well characterized in schizophrenia and psychotic bipolar disorder. Functional MRI was obtained during an event-related spatial delayed match-to-sample task from 58 healthy individuals, 72 individuals with schizophrenia and 41 people with bipolar I disorder with psychotic features in order to: 1) characterize neural responses during encoding, maintenance and retrieval stages of WM using complementary region-of-interest and whole brain approaches; 2) determine whether schizophrenia and psychotic bipolar disorder exhibit similar abnormalities in WM-related brain function; and 3) elucidate the associations between WM-related brain function, task performance, and neuropsychological functioning. Both schizophrenia and psychotic bipolar disorder groups showed encoding- and maintenance-related impairments in the posterior parietal cortex (PPC) and frontal eye fields (FEF). BOLD response in the PPC and FEF, during encoding and maintenance respectively, was associated with task performance independent of group. Additionally, encoding-related activation in the PPC correlated with general neuropsychological functioning independent of group. Only encoding-related activation in the right ventral striatum differed between schizophrenia and psychotic bipolar disorder; individuals with schizophrenia showed significantly lower activation than both psychotic bipolar disorder and healthy groups. Our results are consistent with emerging evidence implicating PPC dysfunction in WM impairment and suggest interventions targeting neural activation in PPC may improve WM and neuropsychological functioning across psychotic disorders.
The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by semantic memory deficits with relatively preserved motor speech, syntax, and phonology. There is consistent evidence linking focal neurodegeneration of the anterior temporal lobes (ATL) to the semantic deficits observed in svPPA. Less is known about large-scale functional connectivity changes in this syndrome, particularly regarding the interplay between affected and spared language networks that leads to the unique cognitive dissociations typical of svPPA. Using whole-brain, seed-based connectivity on task-free Magnetic Resonance Imaging (MRI) data, we studied connectivity of networks anchored to three left-hemisphere regions crucially involved in svPPA symptomatology: ATL just posterior to the main atrophic area, opercular inferior frontal gyrus, and posterior inferior temporal lobe. First, in 32 healthy controls, these seeds isolated three networks: a ventral semantic network involving anterior middle temporal and angular gyri, a dorsal articulatory-phonological system involving inferior frontal and supramarginal regions, and a third functional connection between posterior inferior temporal and intraparietal regions likely involved in linking visual and linguistic processes. We then compared connectivity strength of these three networks between 16 svPPA patients and the 32 controls. In svPPA, decreased functional connectivity in the ventral semantic network correlated with weak semantic skills, while connectivity of the network seeded from the posterior inferior temporal lobe, though not significantly different between the two groups, correlated with pseudoword reading skills. Increased connectivity between the inferior frontal gyrus and the superior portion of the angular gyrus suggested possible adaptive changes. Our findings have two main implications. First, they support a functional subdivision of the left IPL based on its connectivity to specific language-related regions. Second, the unique neuroanatomical and linguistic profile observed in svPPA provides a compelling model for the functional interplay of these networks, being either up- or down- regulated in response to disease.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
Neuroimaging often involves acquiring high-resolution anatomical images along with other low-resolution image modalities, like diffusion and functional magnetic resonance imaging. Performing gray matter statistics with low-resolution image modalities is a challenge due to registration artifacts and partial volume effects. Gray matter surface based spatial statistics (GS-BSS) has been shown to provide higher sensitivity using gray matter surfaces compared to that of skeletonization approach of gray matter based spatial statistics which is adapted from tract based spatial statistics in diffusion studies. In this study, we improve upon GS-BSS incorporating neurite orientation dispersion and density imaging (NODDI) based search (denoted N-GSBSS) by 1) enhancing metrics mapping from native space, 2) incorporating maximum orientation dispersion index (ODI) search along surface normal, and 3) proposing applicability to other modalities, such as functional MRI (fMRI). We evaluated the performance of N-GSBSS against three baseline pipelines: volume-based registration, FreeSurfer's surface registration and ciftify pipeline for fMRI and simulation studies. First, qualitative mean ODI results are shown for N-GSBSS with and without NODDI based search in comparison with ciftify pipeline. Second, we conducted one-sample t-tests on working memory activations in fMRI to show that the proposed method can aid in the analysis of low resolution fMRI data. Finally we performed a sensitivity test in a simulation study by varying percentage change of intensity values within a region of interest in gray matter probability maps. N-GSBSS showed higher sensitivity in the simulation test compared to the other methods capturing difference between the groups starting at 10% change in the intensity values. The computational time of N-GSBSS is 68 times faster than that of traditional surface-based or 86 times faster than that of ciftify pipeline analysis.
Copyright © 2019 Elsevier Inc. All rights reserved.