ObjectiveAutoimmune encephalitis is most frequently associated with anti‐NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid (CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody‐producing clones, and characterize their antibody signatures in recombinant form.MethodsPatients with recent onset typical anti‐NMDAR encephalitis were subjected to flow cytometry analysis of the peripheral and intrathecal immune response before, during, and after immunotherapy. Recombinant human monoclonal antibodies (rhuMab) were cloned and expressed from matching immunoglobulin heavy‐ (IgH) and light‐chain (IgL) amplicons of clonally expanded intrathecal plasma cells (cePc) and tested for their pathogenic relevance.ResultsIntrathecal accumulation of B and plasma cells corresponded to the clinical course. The presence of cePc with hypermutated antigen receptors indicated an antigen‐driven intrathecal immune response. Consistently, a single recombinant human GluN1‐specific monoclonal antibody, rebuilt from intrathecal cePc, was sufficient to reproduce NMDAR epitope specificity in vitro. After intraventricular infusion in mice, it accumulated in the hippocampus, decreased synaptic NMDAR density, and caused severe reversible memory impairment, a key pathogenic feature of the human disease, in vivo.InterpretationA CNS‐specific humoral immune response is present in anti‐NMDAR encephalitis specifically targeting the GluN1 subunit of the NMDAR. Using reverse genetics, we recovered the typical intrathecal antibody signature in recombinant form, and proved its pathogenic relevance by passive transfer of disease symptoms from man to mouse, providing the critical link between intrathecal immune response and the pathogenesis of anti‐NMDAR encephalitis as a humorally mediated autoimmune disease.

IntroductionSubspecies of apolipoproteins can be defined by fractionating apolipoproteins based on the presence and absence of coexisting apolipoproteins.MethodsWe determined age- and sex-adjusted correlations of enzyme-linked immunosorbent assay–measured plasma and cerebrospinal fluid (CSF) apolipoproteins (apoA-I, apoC-III, apoE, and apoJ) or apolipoprotein subspecies (apoA-I with and without apoC-III, ApoE, or apoJ; apoE with and without apoC-III or apoJ) in 22 dementia-free participants.ResultsCSF apoE did not correlate with plasma apolipoproteins or their subspecies. CSF apoJ correlated most strongly with plasma apoA-I without apoJ (r = 0.7). CSF apoA-I correlated similarly strong with plasma total apoA-I and all apoA-I subspecies (r ≥ 0.4) except for apoA-I with apoE (r = 0.3) or apoA-I with apoJ (r = 0.3). CSF apoC-III was most strongly correlated with plasma apoA-I with apoC-III (r = 0.7).DiscussionCSF levels of some apolipoproteins implicated in the pathophysiology of dementia might be better approximated by specific plasma apolipoprotein subspecies than total plasma concentrations.

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ObjectiveTo report an unusual clinical phenotype of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis and describe associated neuropathologic findings.MethodsWe retrospectively investigated 3 AMPAR encephalitis patients with autoimmune global hippocampal amnesia using comprehensive cognitive and neuropsychologic assessment, antibody testing by in-house tissue-based and cell-based assays, and neuropathologic analysis of brain autopsy tissue including histology and immunohistochemistry.ResultsThree patients presented with acute-to-subacute global amnesia without affection of cognitive performance, attention, concentration, or verbal function. None of the patients had epileptic seizures, change of behavior, personality changes, or psychiatric symptoms. The MRI was normal in 1 patient and showed increased fluid-attenuated inversion recovery/T2 signal in the hippocampus in the other 2 patients. Two patients showed complete remission after immunotherapy. The one patient who did not improve had an underlying adenocarcinoma of the lung and died 3.5 months after disease onset because of tumor progression. Neuropathologic analysis of the brain autopsy revealed unilateral hippocampal sclerosis accompanied by mild inflammatory infiltrates, predominantly composed of T lymphocytes, and decrease of AMPAR immunoreactivity.ConclusionAMPAR antibodies usually associate with limbic encephalitis but may also present with immune responsive, acute-to-subacute, isolated hippocampal dysfunction without overt inflammatory CSF or MRI changes.

Objective Cerebral Amyloid Angiopathy (CAA) is a common cause of lobar and subarachnoid hemorrhages in the elderly. A diagnosis of CAA requires multiple lobar hemorrhagic lesions (intracerebral hemorrhage and/or cerebral microbleeds) and/or cortical superficial siderosis (cSS). In contrast hemorrhagic lesions located in the deep structures are the hallmark of hypertensive arteriopathy (HTN-A).They are an exclusion criterion for CAA, and whne present with lobar hemorrhagic lesions considered a separate entity: mixed location hemorrhages/microbleeds (MLH). We compared clinical, radiological and cerebrospinal fluid (CSF) marker data in patients with CAA, MLH, and Alzheimer’s Disease (AD) and healthy controls (HC) and used it to position MLH in the disease spectrum. Patients and Methods Retrospective cohort study of consecutive patients with CAA (n=31), MLH (n=31), AD (n=28) and HC (n=30). Analysis of clinical, radiological, CSF biomarker (Aß42, Aß40, t-tau and p-tau), and histopathological data in patients each group. Results cSS was significantly more common in CAA than MLH (45% vs. 13%, p = 0.011), and cSS in MLH was associated with ICH (p = 0.037). Aß42 levels and and the Aß42/Aß40 ratio, diagnostic groups followed the order HC > MLH > CAA > AD and the opposite order for t-tau and p-tau. No clear order was apparent forAß40. Aß40 and Aß42 levels as well as the Aß42/Aß40 ratio were lower in both CAA and MLH patients with cSS than in patients without cSS. Aß40 and Aß42 levels were higher in CAA and MLH patients with lacunar infarcts than in those without. Conclusion Our data suggest that MLH and CAA are mutually not exclusive diagnoses, and are part of a spectrum with variable contributions of both CAA and HTN-A.

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Objective: Sensorimotor gating is experimentally operationalized by the prepulse inhibition (PPI) of the startle response (SR). Previous studies suggest high test-retest reliability of PPI and potential correlation with working memory (WM). Here we aimed to validate and extend the test-retest reliability of PPI in healthy humans and its correlation with working memory (WM) performance. Methods: We applied an acoustic startle PPI paradigm with four different prepulse intensities (64, 68, 72, and 76 dB) and two different WM tasks (n-back, change detection task [CDT]) in a group of 26 healthy adults (final sample size n=23). To assess test-retest reliability, we performed all tests on two separate days 28 days apart. Results: We were able to confirm high test-retest-reliability of the PPI with a mean intraclass correlation (ICC) of >0.80 and significant positive correlation of PPI with n-back but not with CDT performance. Detailed analysis showed that PPI across all prepulse intensities significantly correlated with both the 2-back and 0-back conditions, suggesting regulation by cross-conditional processes (e.g. attention). However, when removing the 0-back component from the 2-back data, we found a specific and significant correlation with WM for the 76 dB PPI condition. Conclusion: With the present study we were able to confirm the high test-retest reliability of the PPI in humans and could validate and expand on its correlation with WM performance.

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