113 research outputs found

    Network-wide abnormalities explain memory variability in hippocampal amnesia

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    Patients with hippocampal amnesia play a central role in memory neuroscience but the neural underpinnings of amnesia are hotly debated. We hypothesized that focal hippocampal damage is associated with changes across the extended hippocampal system and that these, rather than hippocampal atrophy per se, would explain variability in memory between patients. We assessed this hypothesis in a uniquely large cohort of patients (n = 38) after autoimmune limbic encephalitis, a syndrome associated with focal structural hippocampal pathology. These patients showed impaired recall, recognition and maintenance of new information, and remote autobiographical amnesia. Besides hippocampal atrophy, we observed correlatively reduced thalamic and entorhinal cortical volume, resting-state inter-hippocampal connectivity and activity in posteromedial cortex. Associations of hippocampal volume with recall, recognition, and remote memory were fully mediated by wider network abnormalities, and were only direct in forgetting. Network abnormalities may explain the variability across studies of amnesia and speak to debates in memory neuroscience

    Regulatory T cell profiles in patients with N-methyl-ᴅ-aspartate receptor-antibody encephalitis

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    Purpose Purpose Regulatory T cells (Tregs) have been implicated in the pathogenesis of several autoimmune disorders and used in adoptive cell transfer therapies. Neither have been explored in patients with autoimmune encephalitis where treated patient outcomes remain suboptimal with frequent relapses. Here, to identify new treatment strategies for autoimmune encephalitis, we sought to evaluate the proportion of circulating Tregs and Treg subpopulations in peripheral blood of patients with N-methyl-ᴅ-aspartate receptor-antibody encephalitis (NMDAR-Ab-E) and compared this with healthy controls. Methods We compared the phenotype of peripheral blood Tregs in four adult NMDAR-Ab-E patients and four age- and sex-matched healthy controls using an 11-color flow cytometry assay panel for characterization of Tregs (CD4+ CD25+ FoxP3+) cells into naïve (chemokine receptor [CCR] 7+ CD45RA+), central memory (CCR7+ CD45RA–), and effector memory (CCR7– CD45RA–) cells. We also examined and compared the expression of the CCR6 by circulating Tregs and the respective Treg subpopulations between the study groups. Results The proportion of circulating Tregs was similar between patients with NMDAR-Ab-E and healthy controls but the proportion of naïve Tregs was lower in NMDAR-Ab-E patients (p = 0.0026). Additionally, the frequency of circulating effector memory Tregs was higher, and the proportion of circulating effector memory Tregs expressing CCR6 was lower, in NMDAR-Ab-E patients compared with healthy controls (p = 0.0026). Conclusion Altered Treg homeostasis may be a feature of patients with NMDAR-Ab-E. Future studies with larger samples are warranted to validate these findings

    Pathologic tearfulness after limbic encephalitis: A novel disorder and its neural basis

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    Objective We investigated the nature and neural foundations of pathologic tearfulness in a uniquely large cohort of patients who had presented with autoimmune limbic encephalitis (aLE). Methods We recruited 38 patients (26 men, 12 women; median age 63.06 years; interquartile range [IQR] 16.06 years) in the postacute phase of aLE who completed questionnaires probing emotion regulation. All patients underwent structural/functional MRI postacutely, along with 67 age- and sex-matched healthy controls (40 men, 27 women; median age 64.70 years; IQR 19.87 years). We investigated correlations of questionnaire scores with demographic, clinical, neuropsychological, and brain imaging data across patients. We also compared patients diagnosed with pathologic tearfulness and those without, along with healthy controls, on gray matter volume, resting-state functional connectivity, and activity. Results Pathologic tearfulness was reported by 50% of the patients, while no patient reported pathologic laughing. It was not associated with depression, impulsiveness, memory impairment, executive dysfunction in the postacute phase, or amygdalar abnormalities in the acute phase. It correlated with changes in specific emotional brain networks: volume reduction in the right anterior hippocampus, left fusiform gyrus, and cerebellum, abnormal hippocampal resting-state functional connectivity with the posteromedial cortex and right middle frontal gyrus, and abnormal hemodynamic activity in the left fusiform gyrus, right inferior parietal lobule, and ventral pons. Conclusions Pathologic tearfulness is common following aLE, is not a manifestation of other neuropsychiatric features, and reflects abnormalities in networks of emotion regulation beyond the acute hippocampal focus. The condition, which may also be present in other neurologic disorders, provides novel insights into the neural basis of affective control and its dysfunction in disease

    Hippocampal network abnormalities explain amnesia after VGKCC-Ab related autoimmune limbic encephalitis

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    Objective Limbic encephalitis associated with antibodies to components of the voltage-gated potassium channel complex (VGKCC-Ab-LE) often leads to hippocampal atrophy and persistent memory impairment. Its long-term impact on regions beyond the hippocampus, and the relationship between brain damage and cognitive outcome, are poorly understood. We investigated the nature of structural and functional brain abnormalities following VGKCC-Ab-LE and its role in residual memory impairment. Method A cross-sectional group study was conducted. Twenty-four VGKCC-Ab-LE patients (20 male, 4 female; mean (SD) age 63.86 (11.31) years) were recruited post-acutely along with age- and sex-matched healthy controls for neuropsychological assessment, structural MRI and resting-state functional MRI (rs-fMRI). Structural abnormalities were determined using volumetry and voxel-based morphometry; rs-fMRI data were analysed to investigate hippocampal functional connectivity (FC). Associations of memory performance with neuroimaging measures were examined. Results Patients showed selective memory impairment. Structural analyses revealed focal hippocampal atrophy within the medial temporal lobes, correlative atrophy in the mediodorsal thalamus, and additional volume reduction in the posteromedial cortex. There was no association between regional volumes and memory performance. Instead, patients demonstrated reduced posteromedial cortico-hippocampal and inter-hippocampal FC, which correlated with memory scores (r = 0.553; r = 0.582, respectively). The latter declined as a function of time since the acute illness (r = -0.531). Conclusion VGKCC-Ab-LE results in persistent isolated memory impairment. Patients have hippocampal atrophy with further reduced mediodorsal thalamic and posteromedial cortical volumes. Crucially, reduced FC of remaining hippocampal tissue correlates more closely with memory function than does regional atrophy

    Antibody-associated epilepsies: Clinical features, evidence for immunotherapies and future research questions.

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    PURPOSE: The growing recognition of epilepsies and encephalopathies associated with autoantibodies against surface neuronal proteins (LGI1, NMDAR, CASPR2, GABABR, and AMPAR) means that epileptologists are increasingly asking questions about mechanisms of antibody-mediated epileptogenesis, and about the use of immunotherapies. This review summarizes clinical and paraclinical observations related to autoimmune epilepsies, examines the current evidence for the effectiveness of immunotherapy, and makes epilepsy-specific recommendations for future research. METHOD: Systematic literature search with summary and review of the identified publications. Studies describing the clinical characteristics of autoantibody-associated epilepsies and treatments are detailed in tables. RESULTS: Literature describing the clinical manifestations and treatment of autoimmune epilepsies associated with neuronal cell-surface autoantibodies (NSAbs) is largely limited to retrospective case series. We systematically summarize the features of particular interest to epileptologists dividing patients into those with acute or subacute encephalopathies associated with epilepsy, and those with chronic epilepsy without encephalopathy. Available observational studies suggest that immunotherapies are effective in some clinical circumstances but outcome data collection methods require greater standardization. CONCLUSIONS: The clinical experience captured suggests that clusters of clinical features associate well with specific NSAbs. Intensive and early immunotherapy is indicated when patients present with autoantibody-associated encephalopathies. It remains unclear how patients with chronic epilepsy and the same autoantibodies should be assessed and treated. Tables in this paper provide a comprehensive resource for systematic descriptions of both clinical features and treatments, and highlight limitations of current studies

    Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis

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    Magnetic resonance imaging has linked chronic voltage-gated potassium channel (VGKC) complex antibody-mediated limbic encephalitis with generalized hippocampal atrophy. However, autoantibodies bind to specific rodent hippocampal subfields. Here, human hippocampal subfield (subiculum, cornu ammonis 1-3, and dentate gyrus) targets of immunomodulation-treated LGI1 VGKC-complex antibody-mediated limbic encephalitis were investigated using in vivo ultra-high resolution (0.39 x 0.39 x 1.0 mm³) 7.0T magnetic resonance imaging [n = 18 patients, 17 patients (94%) positive for LGI1 antibody and one patient negative for LGI1/CASPR2 but positive for VGKC-complex antibodies, mean age: 64.0 ± 2.55 years, median 4 years post-limbic encephalitis onset; n = 18 controls]. First, hippocampal subfield quantitative morphometry indicated significant volume loss confined to bilateral CA3 [F(1,34) = 16.87, P 3 months from symptom onset) were associated with CA3 atrophy. Third, whole-brain voxel-by-voxel morphometry revealed no significant grey matter loss. Fourth, CA3 subfield atrophy was associated with severe episodic but not semantic amnesia for postmorbid autobiographical events that was predicted by variability in CA3 volume. The results raise important questions about the links with histopathology, the impact of the observed focal atrophy on other CA3-mediated reconstructive and episodic mechanisms, and the role of potential antibody-mediated pathogenicity as part of the pathophysiology cascade in humans
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