Biology subjects

Kuchling, J.

Publications and source records attributed to Kuchling, J..

7 recordsLinked to original sources

bioRxiv2026

Spatial navigation impairment beyond episodic memory in autoimmune encephalitis

NMDAR and LGI1 encephalitis are the two most common forms of autoimmune encephalitis and are associated with persistent cognitive sequelae, particularly episodic memory impairment. Patients also report lasting difficulties with spatial orientation and navigation, yet these symptoms remain poorly characterized. Both disorders affect neural systems supporting spatial navigation, including prominent hippocampal pathology alongside cingulate, temporo-parietal, thalamic and cerebellar alterations identified in advanced neuroimaging studies. Here, we therefore investigated the frequency and clinical relevance of spatial navigation impairment in post-acute NMDAR and LGI1 encephalitis, its relationship with episodic memory dysfunction, and its structural correlates. We included 80 post-acute patients from the autoimmune encephalitis outpatient clinic at Charite - Universitatsmedizin Berlin: 50 with NMDAR encephalitis (mean age 35.0 years, range 19-71; 90% female; median 6.9 years from onset) and 30 with LGI1 encephalitis (mean age 63.6 years, range 33-84; 67% male; median 2.7 years from onset). Spatial navigation was assessed using a passive map-assisted task (VIENNA Young) and an active wayfinding task (Sea Hero Quest), and its relationship with verbal episodic memory was examined using the Rey Auditory Verbal Learning Test. Structural MRI analyses assessed cortical thickness, subcortical volumes and diffusion measures in preselected navigation- and memory-related regions. Patients with NMDAR and LGI1 encephalitis performed worse than matched controls on map-assisted navigation, and navigation performance showed strong convergence across the two navigation paradigms. Norm-referenced navigation impairment affected 57% of patients with NMDAR encephalitis and 70% with LGI1 encephalitis. In NMDAR encephalitis, selective navigation impairment was more common than selective memory impairment (41% versus 14%; {chi}2 = 6.26, p = .012), supporting partial dissociation. In LGI1 encephalitis, navigation and memory impairments were similarly frequent and strongly overlapping, with 53% of patients impaired in both domains. Older age was a shared risk factor for navigation impairment. Structurally, NMDAR encephalitis showed partly distinct navigation- and memory-related alteration patterns, with navigation-specific parietal-paracentral and cerebellar abnormalities and memory-specific temporal-hippocampal-thalamic involvement. LGI1 encephalitis showed more widespread, predominantly memory-related alterations without a robust navigation-specific structural signature. Our findings identify spatial navigation as a frequently affected but under-assessed cognitive domain in post-acute NMDAR and LGI1 encephalitis. They provide clinical evidence that navigation and episodic memory are partially dissociable yet overlapping functions whose degree of separability varies with the extent and distribution of network pathology. Incorporating norm-referenced navigation assessment into longitudinal follow-up could improve the characterization of cognitive profiles and related support needs, while reducing the risk that impairments relevant to everyday functioning and long-term quality of life remain undetected.

neuroscience↗

bioRxiv2024

Persistent cognitive deficits in anti-LGI1 encephalitis are linked to a reorganization of structural brain networks

Structured AbstractO_ST_ABSImportanceC_ST_ABSDespite immunotherapy, most patients with anti-leucine-rich, glioma-inactivated 1 encephalitis (LGI1-E) develop long-term cognitive deficits that persist for years after peak illness. However, the structural brain changes that underlie these deficits remain poorly understood. ObjectiveTo study the relationship between cognitive outcomes and white matter (WM) networks in LGI1-E. DesignCross-sectional study. SettingGerman university center (Charite - Universitatsmedizin Berlin). Participants25 patients with LGI1-E (19/25 male [76%], mean age: 63 {+/-} 12 years) and 25 age- and sex-matched healthy controls (HC), recruited between January 2013 and April 2019. Main Outcomes and MeasuresClinical assessments including the modified Rankin Scale (mRS) and Clinical Assessment Scale in Autoimmune Encephalitis (CASE); comprehensive cognitive testing; WM tractography using diffusion-weighted MRI. ResultsAll patients had received first-line immunotherapy, and two-thirds underwent second-line immunotherapy. Patients showed a significant reduction in mRS scores from peak illness to post-acute follow-up (z = -3.8, p < 0.001, n = 20), with 85% presenting "good" functional outcomes (post-acute mRS [≤] 2), paralleled by a significant reduction in CASE scores (z = -3.5, p < 0.001, n = 20). Despite this overall improvement, however, cognitive symptoms were highly prevalent at peak illness (95% of patients affected) and strongly persisted into the post-acute disease stage (85% affected). Neuroimaging at post-acute follow-up (median: 12 months from onset) revealed that LGI1-E is characterized by (i) significantly reduced whole-brain structural connectivity (t = -2.16, p = 0.036, d = -0.61), (ii) a cortico-subcortical hypoconnectivity cluster that strongly affects the hippocampus but also severely impacts extra-limbic brain systems, (iii) systematic limbic and extra-limbic decreases in node degree -- a graph-theoretical measure of overall connectedness, and (iv) a "topological reorganization" of structural brain networks, marked by a bidirectional shift in the relative importance of individual brain regions in the network. Importantly, the extent of this network reorganization was significantly related to persistent cognitive deficits in the domains of verbal memory (r = -0.57, p = 0.007, n = 21), attention (r = -0.47, p = 0.030, n = 21), and executive functions (r = -0.60, p = 0.010, n = 17). Conclusion and RelevanceThis study characterizes LGI1-E as a network disease that affects both limbic and extra-limbic brain systems and shows that a reorganization of WM networks is linked to multi-domain cognitive deficits in the post-acute disease stage - despite immunotherapy and good overall recovery. These findings highlight the need for extended treatment strategies to improve long-term cognitive outcomes and propose a sensitive new neuroimaging marker to include in prospective clinical trials. Key PointsO_ST_ABSQuestionC_ST_ABSWhat structural brain changes underlie the persistent cognitive deficits observed in patients with anti-leucine-rich, glioma-inactivated 1 encephalitis (LGI1-E)? FindingsThis cross-sectional study shows that LGI1-E is characterized by a structural reorganization of white matter networks that affects both limbic and extra-limbic brain systems and correlates with persistent deficits in verbal memory, attention, and executive functions at post-acute follow-up - despite immunotherapy and good overall clinical recovery. MeaningThis study characterizes LGI1-E as a network disease -beyond focal damage to the limbic system- and shows that persistent cognitive deficits relate to immunotherapy-resistant changes in structural brain networks, highlighting the need for extended treatment strategies to improve long-term cognitive outcomes.

neuroscience↗

bioRxiv2023

Maternofetal transfer of human NMDAR antibodies leads to cortical network defect in the adult

Anti-N-methyl-D-aspartate-receptor IgG-antibodies (NMDAR-Ab) can be detected in up to 1% of the healthy population. Because maternal IgG can cross the placental barrier during pregnancy, these antibodies may influence fetal neurodevelopment. Using a mouse model of maternofetally transferred human NMDAR-Ab, we asked whether in utero exposure impacts functional brain dynamics later in life. We conducted two-photon calcium imaging and fMRI in adolescent mice, to evaluate both local and global neuronal network integrity. At the microcircuit scale, NMDAR-Ab exposed offspring exhibited lower spontaneous activity, reduced firing variability, and reduced orientation selectivity upon visual stimulation. Globally, fMRI revealed a selective bilateral functional hypoconnectivity of the entorhinal-hippocampal pathway while overall functional connectivity is unaffected. Together, our data indicates that maternal-fetal transfer of NMDAR-Ab leads to a lasting impairment in sensory processing and memory-routing circuits, revealing a vulnerability of the developing fetal brain to maternal autoantibodies.

neuroscience↗

bioRxiv2023

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

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.

neuroscience↗

bioRxiv2023

Multiscale networks in multiple sclerosis

Complex diseases such as Multiple Sclerosis (MS) cover a wide range of biological scales, from genes and proteins to cells and tissues, up to the full organism. We conducted a multilayer network analysis and deep phenotyping with multi-omics data (genomics, phosphoproteomics and cytomics), brain and retinal imaging, and clinical data, obtained from a multicenter prospective cohort of 328 patients and 90 healthy controls. Multilayer networks were constructed using mutual information, and Boolean simulations identified paths within and among all layers. The path more commonly found from the boolean simulations connects MP2K, with Th17 cells, the retinal nerve fiber layer (RNFL) thickness and the age related MS severity score (ARMSS). Combinations of several proteins (HSPB1, MP2K1, SR6, KS6B1, SRC, MK03, LCK and STAT6)) and immune cells (Th17, Th1 non-classic, CD8, CD8 Treg, CD56 neg, and B memory) were part of the paths explaining the clinical phenotype. Specific paths identified were subsequently analyzed by flow cytometry at the single-cell level. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/530153v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@7dd26org.highwire.dtl.DTLVardef@482239org.highwire.dtl.DTLVardef@1bef03borg.highwire.dtl.DTLVardef@8dc6e6_HPS_FORMAT_FIGEXP M_FIG C_FIG Author SummaryComplex diseases such as Multiple Sclerosis (MS) involve the contribution of a wide range of biological processes. We conducted a systems biology study of MS based on network analysis and deep phenotyping in a prospective cohort of patients with clinical, imaging, genetics, and omics assessments. The gene, proteins and cell paths explained variation in central nervous system damage, and in metrics of disease severity. Such multilayer paths explain the different phenotypes of the disease and can be developed as biomarkers of MS.

systems biology↗

bioRxiv2022

Impaired functional connectivity of the hippocampus in murine models of NMDA-receptor antibody associated pathology

IntroductionWhile decreased hippocampal connectivity and disruption of functional networks are established MRI features in human anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, the underlying pathophysiology for brain network alterations remains poorly understood. Application of patient-derived monoclonal antibodies against the NR1 subunit of the NMDAR allows for the investigation of potential functional connectivity alterations in experimental murine NMDAR antibody disease models. ObjectiveTo explore functional connectivity changes in NR1 antibody mouse models using resting-state functional MRI (rs-fMRI). MethodsAdult C57BL/6J mice (n=10) were intrathecally injected with a recombinant human NR1 antibody over 14 days and then studied using rs-fMRI at 7 Tesla. In addition, a newly established mouse model with in utero exposure to a human recombinant NR1 antibody characterized by a neurodevelopmental disorder (NR1-offspring) was investigated with rs-fMRI at the age of 8 weeks (n=15) and 10 months (n=14). Mice exposed to isotype-matched control antibodies served as controls. Independent component analysis (ICA) and dual regression analysis were performed to compare functional connectivity between NMDAR antibody mouse models and control mice. ResultsAdult NR1-antibody injected mice showed significantly impaired functional connectivity within the dentate gyrus of the left hippocampus in comparison to controls, resembling impaired hippocampal functional connectivity patterns observed in human patients with NMDAR encephalitis. Similarly, analyses showed significantly reduced functional connectivity in the dentate gyrus in NR1-offspring compared after 8 weeks, and impaired connectivity in the dentate gyrus and CA3 hippocampal subregion in NR1-offspring at the age of 10 months. ConclusionFunctional connectivity changes within the hippocampus resulting from both direct application and in utero exposure to NMDAR antibodies can be modeled in experimental murine systems. With this translational approach, we successfully reproduced functional MRI alterations previously observed in human NMDAR encephalitis patients. Future experimental studies will identify the detailed mechanisms that cause functional network alterations and may eventually allow for non-invasive monitoring of disease activity and therapeutic effects in autoimmune encephalitis.

neuroscience↗

bioRxiv2020

Vascular cognitive impairment in the mouse reshapes visual, spatial network functional connectivity.

Connectome analysis of neuroimaging data is a rapidly expanding field to identify disease specific biomarkers. Structural diffusion MRI connectivity has been useful in individuals with radiological features of small vessel disease, such as white matter hyperintensities. Global efficiency, a network metric calculated from the structural connectome, is an excellent predictor of cognitive decline. To dissect the biological underpinning of these changes, animal models are required. We tested whether the structural connectome is altered in a mouse model of vascular cognitive impairment. White matter damage was more pronounced by 6 compared to 3 months. Global efficiency remained intact, but the visual association cortex exhibited increased structural connectivity with other brain regions. Exploratory resting state functional MRI connectivity analysis revealed diminished default mode network activity in the model compared to shams. Further perturbations were observed in a primarily cortical hub and the retrosplenial and visual cortices, and the hippocampus were the most affected nodes. Behavioural deficits were observed in the cued water maze, supporting the suggestion that the visual and spatial memory networks are affected. We demonstrate specific circuitry is rendered vulnerable to vascular stress in the mouse, and the model will be useful to examine pathophysiological mechanisms of small vessel disease. Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗