Changes in Electric Brain Response to Affective Stimuli in the First Week of Antidepressant Treatment: An Exploratory Study

Introduction: Asymmetrical alpha and frontal theta activity have been discussed as neurobiological markers for antidepressant treatment response. While most studies focus on resting-state EEG, there is evidence that task-related activity assessed at multiple time points might be superior in detecting subtle early differences. Methods: This was a naturalistic study design assessing participants in a psychiatric in- and outpatient hospital setting. We investigated stimulus-related EEG asymmetry (frontal and occipital alpha-1 and alpha-2) and power (frontal midline theta) assessed at baseline and 1 week after initiation of pharmacological depression treatment while presenting affective stimuli. We then compared week 4 responders and nonresponders to antidepressant treatment. Results: Follow-up analyses of a significant group x emotion x time interaction (p < 0.04) for alpha-1 asymmetry showed that responders differed significantly at baseline in their asymmetry scores in response to sad compared to happy faces with a change in this pattern 1 week later. Nonresponders did not show this pattern. No significant results were found for alpha-2, occipital alpha-1, and occipital alpha-2 asymmetry or frontal midline theta power. Discussion: Our study addresses the gap in comparisons of task-related EEG activity changes measured at two time points and supports the potential value of this approach in detecting early differences in responders versus nonresponders to pharmacological treatment. Important limitations include the small sample size and the noncontrolled study design

Promoter DNA methylation regulates progranulin expression and is altered in FTLD

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of neurodegenerative diseases associated with personality changes and progressive dementia. Loss-of-function mutations in the growth factor progranulin (GRN) cause autosomal dominant FTLD, but so far the pathomechanism of sporadic FTLD is unclear. RESULTS: We analyzed whether DNA methylation in the GRN core promoter restricts GRN expression and, thus, might promote FTLD in the absence of GRN mutations. GRN expression in human lymphoblast cell lines is negatively correlated with methylation at several CpG units within the GRN promoter. Chronic treatment with the DNA methyltransferase inhibitor 5-aza-2(′)-deoxycytidine (DAC) strongly induces GRN mRNA and protein levels. In a reporter assay, CpG methylation blocks transcriptional activity of the GRN core promoter. In brains of FTLD patients several CpG units in the GRN promoter are significantly hypermethylated compared to age-matched healthy controls, Alzheimer and Parkinson patients. These CpG motifs are critical for GRN promoter activity in reporter assays. Furthermore, DNA methyltransferase 3a (DNMT3a) is upregulated in FTLD patients and overexpression of DNMT3a reduces GRN promoter activity and expression. CONCLUSION: These data suggest that altered DNA methylation is a novel pathomechanism for FTLD that is potentially amenable to targeted pharmacotherapy

Multicentre comparison of a diagnostic assay: Aquaporin-4 antibodies in neuromyelitis optica

Objective Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD). Methods Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1). Results Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples. Conclusions The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology

Test-Retest Reliability of Frontal and Parietal Alpha Asymmetry during Presentation of Emotional Face Stimuli in Healthy Subjects

Resting-state and event-related frontal alpha asymmetry have been suggested as potential neurobiological biomarkers for depression and other psychiatric conditions. To be used as such, sufficient test-retest reliability needs to be demonstrated. However, test-retest reliability is underinvestigated for event-related alpha asymmetry. The objective of this study was to examine both short-term within-session and long-term between-session reliability of stimulus-related medial and lateral frontal as well as parietal alpha EEG asymmetry in healthy subjects during a simple emotional face processing task. Twenty-three healthy adults participated in two sessions with a test-retest interval of about 1 week. Reliability was estimated with Pearson's correlation coefficient and paired t test. Results revealed moderate to high within-session reliability of stimulus-related alpha asymmetry for all electrode sites and both conditions. Alpha asymmetry mean values did not change significantly within sessions. Between-session reliability was fair for frontomedial and moderate for frontolateral stimulus-related asymmetry. Exploratory exclusion of subjects with unstable between-session self-rating scores of emotional state and empathy toward stimuli resulted in some higher reliability values. Our results indicate that stimulus-related alpha asymmetry may serve as a useful electrophysiological tool given its adequate within-session reliability. However, long-term stability of stimulus-related frontal alpha asymmetry over 1 week was comparatively low and varied depending on electrode position. Influencing state factors during EEG recording, such as current mood or stimulus engagement, should be considered in future study designs and analyses. Further, we recommend to analyze alpha asymmetry from both frontomedial and frontolateral sites

Cerebrospinal Fluid Homer-3 Autoantibodies in a Patient with Amnestic Mild Cognitive Impairment

(1) Background: Homer-3 antibodies are associated with cerebellar disease ranging from subacute degeneration to cerebellitis. However, cognitive impairment associated with Homer-3 autoantibodies has not been reported until now. (2) Methods: in retrospect, we systematically studied clinical, cranial magnetic resonance imaging (cMRI), electroencephalography (EEG) and lumbar puncture data, including neural autoantibodies of a clinical case. (3) Results: we describe the case of a 56-year-old woman presenting with amnestic mild cognitive impairment in association with serum and CSF detection of Homer-3 autoantibodies and a depressive syndrome. cMRI revealed cerebellar atrophy. CSF analysis showed elevated ptau181 protein. Applying the criteria for an autoimmune psychiatric syndrome revealed a plausible autoimmune basis for the mild cognitive impairment. (4) Discussions: our case report demonstrates an amnestic mild cognitive impairment and depressive symptoms associated with Homer-3 autoantibodies as a novel feature of Homer-3 antibody-related disease. We also propose that cognitive dysfunction might result from impaired AMPAR signaling in the hippocampus induced by Homer-3 antibodies, which will have to be verified in further research

Long-Term Course of Neural Autoantibody-Associated Psychiatric Disorders: Retrospective Data from a Specifically Immunopsychiatric Outpatient Clinic

Background: Autoantibody-associated psychiatric disorders are a new terrain that is currently underrepresented considering immunopsychiatry’s potential importance for therapeutic aspects. The aim of our research was thus to present initial pilot data on the long-term clinical course of our patients in an outpatient clinic specializing in autoantibody-associated psychiatric disorders. Methods: Thirty-seven patients were examined clinically in our outpatient clinic at regular intervals over a 1.5-year period. We collected clinical data on their demographics, psychopathology, and cognition, and magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) data as well as the status of neural autoantibodies in blood and/or serum. Results: Our main finding was that affective, psychotic, and cognitive symptoms did not change significantly over the 1.5-year period, thus revealing no progression. We divided the entire cohort of autoantibody-positive patients (n = 32) into subgroups consisting of patients with dementia (n = 14), mild cognitive impairment (MCI) (n = 7), psychotic disorders (n = 6), and a CSF profile of Alzheimer’s disease (n = 6). Relying on established classification schemes, we identified the following percentages in our autoantibody-positive cohort: 28% with autoimmune encephalitis, 15% with autoimmune psychosis, and 63% with autoimmune psychiatric syndromes. Discussion: These initial pilot results suggest that autoantibody-associated diseases do not show a significantly progressive course in the long-term and are often characterized by impaired verbal memory recall when cognitive impairment progresses to dementia. These initial data need to be verified in larger cohorts. We believe that this pilot study underscores the importance of promoting such a specialized outpatient clinic to better characterize various aspects of autoantibody-mediated psychiatric disorders

Case report: Amnestic mild cognitive impairment in multiple domains associated with neurofascin 186 autoantibodies: Case series with follow-up and review

BACKGROUND: Neurofascin 186 autoantibodies are known to occur with a diseased peripheral nervous system. Recently, also additional central nervous system (CNS) involvement has been reported in conjunction with neurofascin 186 autoantibodies. Our case enlarges the spectrum of neurofascin 186 antibody-related disease to include mild cognitive impairment (MCI). METHODS: We report here a case after having examined the patient files retrospectively, including diagnostics such as blood and cerebrospinal fluid (CSF) analysis involving the determination of neural autoantibodies, brain magnetic resonance imaging (MRI), brain fluorodesoxyglucose positron emission tomography (FDG-PET), and extensive neuropsychological testing. RESULTS: We report on two patients with MCI. Brain MRI showed cerebral microangiopathy in both patients, but brain FDG-PET demonstrated pathology in the right prefrontal cortex, in the right inferior parietal cortex, and in both lateral occipital cortices in one patient. Neurofascin 186 antibodies were detected in serum in both patients, and neurofascin 186 autoantibodies were also detected in the CSF of one of these patients. At follow-up six month later, neurofascin 186 autoantibodies disappeared in one patient while persisting in the other. CONCLUSION: We report on two individuals presenting MCI associated with neurofascin 186 antibodies, thus expanding the potential spectrum of neurofascin 186-associated disease. This report supports the recommendation to consider also neurofascin 186 autoantibodies in not just peripheral nerve disease, but also in disorders involving CNS autoimmunity. More studies are needed to clarify the lack of association between neurofascin 186 autoantibodies and cognitive decline

Persisting Verbal Memory Encoding and Recall Deficiency after mGluR5 Autoantibody-Mediated Encephalitis

Background: Metabotropic glutamate receptors type 5 (mGluR5) play a central role in persistent forms of synaptic plasticity and memory formation. Antibodies to mGluR5 have been reported to be clinically associated with memory impairment. Here, we report on a patient with persistent amnestic cognitive impairment in a single cognitive domain after resolution of mGluR5-associated encephalitis. Methods: We report on the clinical data of a patient in our Department of Psychiatry and Psychotherapy who underwent several diagnostic investigations including a detailed neuropsychological examination, magnetic resonance imaging, and cerebrospinal fluid analysis involving the determination of neural autoantibodies. Results: A 54-year-old woman presented to our memory clinic with pleocytosis 4 months after remission of probable anti-mGluR5-mediated encephalitis, revealing initial pleocytosis and serum proof of anti-mGluR5 autoantibodies (1:32). A neuropsychological examination revealed mild cognitive impairment in verbal memory encoding and recall. The patient received immunotherapy with corticosteroids, and a subsequent cerebrospinal fluid analysis 1.5 months after the onset of encephalitis confirmed no further signs of inflammation. Conclusions: Our results suggest that although immunotherapy resulted in the remission of anti-mGluR5 encephalitis, a verbal memory encoding and recall dysfunction persisted. It remains unclear whether the reason for the persistent verbal memory impairment is attributable to insufficiently long immunotherapy or initially ineffective immunotherapy. Because mGluR5 plays an essential role in persistent synaptic plasticity in the hippocampus, it is tempting to speculate that the mGluR5 antibody–antigen complex could lead to persistent cognitive dysfunction, still present after the acute CNS inflammation stage of encephalitis

Development of a Recombinant Cell-Based Indirect Immunofluorescence Assay for the Determination of Autoantibodies against Soluble Liver Antigen in Autoimmune Hepatitis

Autoantibodies against soluble liver antigen (SLA) are specific markers for autoimmune hepatitis (AIH) type 1. In contrast to the determination of other AIH-associated autoantibodies by indirect immunofluorescence assay (IFA), detection of anti-SLA relied up to now on ELISA or immunoblot based on bacterially expressed recombinant protein. In order to develop a complementary IFA substrate, SLA isoform 1 was recombinantly produced in the human cell line HEK293 and controlled by a rabbit hyperimmune serum against SLA. The recombinant cells were used in IFA (RC-IFA) to analyze sera from 20 AIH patients with anti-SLA positivity predetermined by ELISA together with 80 controls (20 anti-SLA negative AIH, 15 primary biliary cirrhosis, 15 HCV, and 30 healthy blood donors). Using RC-IFA, anti-SLA was detected in all ELISA positive AIH sera but in none of the controls. Furthermore, a cytosolic fraction of HEK293 containing SLA was able to neutralize the autoantibodies in all positive sera in a dose-dependent manner. HEK293 cells expressing SLA are a valid substrate for the serodiagnosis of AIH relevant autoantibodies by IFA. In concert with cryosections of primate liver, rat kidney, rat liver, rat stomach, and HEp-2 cells, they enable the parallel determination of all autoantibodies associated with autoimmune liver diseases