In Vivo <i>N</i>-Methyl-<scp>d</scp>-Aspartate Receptor (NMDAR) Density as Assessed Using Positron Emission Tomography During Recovery From NMDAR-Antibody Encephalitis

Galovic, Marian; Al-Diwani, Adam; Vivekananda, Umesh; Walker, Matthew; Irani, Sarosh; Koepp, Matthias J.

doi:10.1001/jamaneurol.2022.4352

Cited by 9 publications

(4 citation statements)

References 7 publications

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“…In addition, FDG-PET imaging revealed precuneus hypometabolism in six NMDAR encephalitis patients [60]. A recent study using [ 18 F]GE-179 PET identified a reduction in the density of open, active NMDARs in the anterior temporal lobes, superior parietal cortices and in the precuneus [61], lending further support to the notion of functional impairment of the precuneus in NMDAR encephalitis.…”

Section: Discussionmentioning

confidence: 61%

Hippocampal hub failure is linked to long-term memory impairment in anti-NMDA-receptor encephalitis - Insights from structural connectome graph theoretical network analysis

Hechler,

Kuchling,

Müller-Jensen

et al. 2023

Preprint

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IntroductionAnti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is characterized by distinct structural and functional brain alterations, predominantly affecting the medial temporal lobes and the hippocampus. Structural connectome analysis with graph-based investigations of network properties allows for an in-depth characterization of global and local network changes and their relationship with clinical deficits in NMDAR encephalitis.ObjectiveTo investigate changes in structural connectivity and network efficiency in NMDAR encephalitis by use of probabilistic whole-brain tractography and graph theoretical analysis of structural brain networks.MethodsStructural networks from sixty-one NMDAR encephalitis patients in the post-acute stage (median time from acute hospital discharge: 18 months) and sixty-one age- and sex-matched healthy controls (HC) were analyzed using diffusion-weighted imaging (DWI)-based probabilistic anatomically-constrained tractography and spherical deconvolution-informed filtering of tractograms. We calculated global, modular, and nodal graph measures indicative of structural connectivity and network reorganization with special focus on default-mode network, medial temporal lobe, and hippocampus. Pathologically altered metrics were included in multiple regression analyses to investigate their potential association with clinical course, disease severity, and cognitive outcome.ResultsPatients with NMDAR encephalitis showed regular global graph metrics, but bilateral reductions of hippocampal node strength (left:p=0.049; right:p=0.013) and increased node strength of right precuneus (p=0.013) compared to HC. Betweenness centrality was decreased for left-sided entorhinal cortex (p=0.042) and left caudal middle frontal gyrus (p = 0.037). Correlation analyses showed a significant association between reduced left hippocampal node strength and verbal long-term memory impairment (p=0.021)ConclusionFocal network property changes of the medial temporal lobes indicate hippocampal hub failure that is associated with memory impairment in NMDAR encephalitis at the post-acute stage, while global structural network properties remain unaltered. Graph theory analysis provides new pathophysiological insight into structural network changes and their association with persistent cognitive deficits in NMDAR encephalitis.

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Section: Discussionmentioning

confidence: 61%

Hippocampal hub failure is linked to long-term memory impairment in anti-NMDA-receptor encephalitis - Insights from structural connectome graph theoretical network analysis

Hechler,

Kuchling,

Müller-Jensen

et al. 2023

Preprint

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“…Following the combination of methotrexate and rituximab, the trajectory of the short-period component increased. Considering the plasma membrane origin of EV membranes and previous reports of NMDAR density reduction in anti-NMDAR encephalitis patients and its restoration upon effective treatment 75 , we hypothesize that this short-period signal may reflected the dynamic response of NMDAR density on astrocyte plasma membranes to treatment. However, it is important to note that definitive conclusions cannot be drawn from a single case in this study, the aforementioned conjectures are more suitable as new hypotheses for further investigation.…”

Section: Discussionmentioning

confidence: 72%

Urinary Astrocyte-derived Extracellular Vesicles: A Non-invasive Tool for Capturing HumanIn VivoMolecular “Movies” of Brain

Xie,

Chen,

et al. 2024

Preprint

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The identification of particularly individual-level biomarkers, for certain central nervous system (CNS) diseases remains challenging. A recent approach involving the enrichment of brain-derived extracellular vesicles (BDEVs) from peripheral blood has emerged as a promising method to obtain direct in vivo CNS data, bypassing the blood-brain barrier. However, for rapidly evolving CNS diseases (e.g., weeks or even days), the Nyquist-Shannon sampling theorem dictates the need for a high-frequency sampling rate. Obviously, daily collection of blood or cerebrospinal fluid from human subjects is impractical. Thus, we innovated a novel method to isolate astrocyte-derived EVs from urine (uADEVs). It involves three main steps: 1) concentrating urine samples, 2) isolating total EVs from urine (uTEVs) using ultracentrifugation, and 3) using an anti-glutamate/aspartate transporter (GLAST) antibody to isolate GLAST+EVs from uTEVs. Subsequently, we confirmed the identity of these GLAST+EVs as uADEVs using transmission electron microscopy, nanoparticle tracking analysis, western blotting, and the measurement of astrocyte-related neurotrophins. Furthermore, we applied the uADEVs protocol to depict the detailed trajectory of the N-methyl-d-aspartic acid receptor (NMDAR) subunit zeta-1 (GluN1) in an anti-NMDAR encephalitis patient, demonstrated the potential of this method for capturing intricate trajectories of CNS-specific molecular in vivo signals at the individual level. This non-invasive approach enables frequent sampling, up to daily or even half-daily, analogous to capturing molecular "movies" of the brain, coupled with appropriate signal processing algorithms, holds promise for identifying novel biomarkers or illuminating the etiology of rapidly evolving CNS diseases by tracking the precise trajectories of target molecules.

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“…Using a PET ligand which targets activated NMDARs, it was observed that patients recovering from NMDAR-AbE showed a reduction in NMDAR density which correlated with time from disease onset. One patient, who was both furthest into their recovery and had no detectable NMDAR-antibodies, had NMDAR densities equivalent to controls [112]. Hence, imaging tools might be useful to monitor in vivo recovery and could inform longer term treatment decisions.…”

Section: Monitoring Diseasementioning

confidence: 97%

Autoimmune encephalitis: recent clinical and biological advances

et al. 2023

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In 2015, we wrote a review in The Journal of Neurology summarizing the field of autoantibody-associated neurological diseases. Now, in 2023, we present an update of the subject which reflects the rapid expansion and refinement of associated clinical phenotypes, further autoantibody discoveries, and a more detailed understanding of immunological and neurobiological pathophysiological pathways which mediate these diseases. Increasing awareness around distinctive aspects of their clinical phenotypes has been a key driver in providing clinicians with a better understanding as to how these diseases are best recognized. In clinical practice, this recognition supports the administration of often effective immunotherapies, making these diseases ‘not to miss’ conditions. In parallel, there is a need to accurately assess patient responses to these drugs, another area of growing interest. Feeding into clinical care are the basic biological underpinnings of the diseases, which offer clear pathways to improved therapies toward enhanced patient outcomes. In this update, we aim to integrate the clinical diagnostic pathway with advances in patient management and biology to provide a cohesive view on how to care for these patients in 2023, and the future.

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In Vivo N-Methyl-d-Aspartate Receptor (NMDAR) Density as Assessed Using Positron Emission Tomography During Recovery From NMDAR-Antibody Encephalitis

Abstract: This case-control study uses a radiotracer and positron emission tomography to assess N-methyl-d-aspartate receptor (NMDAR) density changes during recovery from NMDAR-antibody encephalitis.

Cited by 9 publications

References 7 publications

Hippocampal hub failure is linked to long-term memory impairment in anti-NMDA-receptor encephalitis - Insights from structural connectome graph theoretical network analysis

Hippocampal hub failure is linked to long-term memory impairment in anti-NMDA-receptor encephalitis - Insights from structural connectome graph theoretical network analysis

Urinary Astrocyte-derived Extracellular Vesicles: A Non-invasive Tool for Capturing HumanIn VivoMolecular “Movies” of Brain

Autoimmune encephalitis: recent clinical and biological advances

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