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Post-COVID-19 syndrome is a serious complication following SARS-CoV-2 infection, characterized primarily by fatigue and cognitive complaints. Although first metabolic and structural imaging alterations in Post-COVID-19 syndrome have been identified, their functional consequences remain unknown. Thus, we explored the impact of Post-COVID-19 syndrome on the functional connectome of the brain providing a deeper understanding of pathophysiological mechanisms. In a cross-sectional observational study, resting-state functional magnetic resonance imaging data of 66 patients with Post-COVID-19 syndrome after mild infection (mean age 42.3 years, 57 female) and 57 healthy controls (mean age 42.1 years, 38 female) with a mean time of seven months after acute COVID-19 were analysed using a graph theoretical approach. Network features were quantified using measures including mean distance, nodal degree, betweenness and Katz centrality, and compared between both groups. Graph measures were correlated with clinical measures quantifying fatigue, cognitive function, affective symptoms and sleep disturbances. Alterations were mainly found in the brainstem, olfactory cortex, cingulate cortex, thalamus and cerebellum on average seven months after SARS-CoV-2 infection. Additionally, strong correlations between fatigue severity, cognitive functioning and daytime sleepiness from clinical scales and graph measures were observed. Our study confirms functional relevance of brain imaging changes in Post-COVID-19 syndrome as mediating factors for persistent symptoms and improves our pathophysiological understanding.

Background Since 2020, several specialized follow-up outpatient clinics have been established across Germany to address the complex needs of patients with Long COVID/ Post-COVID-19 Condition (PCC). This article reviews the current landscape of these specialized clinics in Germany and critically evaluates their diagnostic and treatment algorithms. Methods This study employed a mixed-method approach, combining publicly available information on post-COVID-19 outpatient clinics with an observational cross-sectional online survey among lead doctors of PCC follow-up outpatient clinics in Germany. The survey was conducted from November 2023 to January 2024. Descriptive statistics and t-tests for group-comparisons were employed, with statistical significance set at p  < 0.05. Results At the time of the survey, 112 specialized PCC outpatient clinics were identified in Germany through publicly available information. Forty-five PCC outpatient clinic lead doctors (40.2%) responded to our survey. Treatment of PCC patients is personalized and symptom-oriented rather than standardized. Patient characteristics of the two identified main treatment domains, focusing on respiratory and neurocognitive symptoms, differed only in sex distribution. A higher proportion of females (63.9%) presented with pulmonary symptoms compared to patients with neurocognitive impairments (50.2%, p  < 0.05). The level of distress among patients is generally perceived as high and outpatient clinic lead doctors are convinced that their outpatient counseling services offer significant benefits. Conclusions As the demand for PCC follow-up outpatient clinics persists, the establishment of new services continues, particularly to address the growing need for neurocognitive care services. PCC outpatient care is currently personalized and symptom-orientated, leading to high variability across clinics. Further standardization of treatment protocols and diagnostic algorithms could improve patient care and facilitate professional exchange.

Background Deep phenotyping and longitudinal assessment of predementia at-risk states of Alzheimer’s disease (AD) are required to define populations and outcomes for dementia prevention trials. Subjective cognitive decline (SCD) is a pre-mild cognitive impairment (pre-MCI) at-risk state of dementia, which emerges as a highly promising target for AD prevention. Methods The German Center for Neurodegenerative Diseases (DZNE) is conducting the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE), which focuses on the characterization of SCD in patients recruited from memory clinics. In addition, individuals with amnestic MCI, mild Alzheimer’s dementia patients, first-degree relatives of patients with Alzheimer’s dementia, and cognitively unimpaired control subjects are studied. The total number of subjects to be enrolled is 1000. Participants receive extensive clinical and neuropsychological assessments, magnetic resonance imaging, positron emission tomography, and biomaterial collection is perfomed. In this publication, we report cognitive and clinical data as well as apolipoprotein E (APOE) genotype and cerebrospinal fluid (CSF) biomarker results of the first 394 baseline data sets. Results In comparison with the control group, patients with SCD showed slightly poorer performance on cognitive and functional measures (Alzheimer’s Disease Assessment Scale—cognitive part, Clinical Dementia Rating, Functional Activities Questionnaire), with all mean scores in a range which would be considered unimpaired. APOE4 genotype was enriched in the SCD group in comparison to what would be expected in the population and the frequency was significantly higher in comparison to the control group. CSF Aβ42 was lower in the SCD group in comparison to the control group at a statistical trend with age as a covariate. There were no group differences in Tau or pTau concentrations between the SCD and the control groups. The differences in all measures between the MCI group and the AD group were as expected. Conclusions The initial baseline data for DELCODE support the approach of using SCD in patients recruited through memory clinics as an enrichment strategy for late-stage preclinical AD. This is indicated by slightly lower performance in a range of measures in SCD in comparison to the control subjects as well as by enriched APOE4 frequency and lower CSF Aβ42 concentration. Trial registration German Clinical Trials Register DRKS00007966 . Registered 4 May 2015.

Neurological post-COVID condition (PCC) often involves attentional deficits that impact daily functioning. Traditional paper-based tests, like the Trail-Making Test (TMT), may inadequately capture these impairments due to their short duration and dependence on numerical and alphabetic sequencing. This study evaluates the validity of three subtests of the computerized Test for Attentional Performance (TAP) as alternatives for detecting attentional impairments in PCC. In the ongoing NEURO LC-19 DE study, 108 subjects aged 18 to 79 years, with PCC-related cognitive complaints ( n  = 67, 73% f) and healthy controls ( n  = 41, 56% f) underwent neuropsychological testing. The prevalence of impairment and classification ability of the TAP subtests were evaluated alongside standard paper-based tests, including the TMT and Montreal Cognitive Assessment, using receiver operating characteristic (ROC) analysis and regression. The TAP subtests identified significant impairments in sustained attention and processing speed in one-third of PCC patients, surpassing traditional tests in sensitivity, and classifying PCC with an AUC of 78%. Omissions in sustained attention significantly differentiated groups (OR = 1.14, p  = 0.016, 95% CI [1.02–1.26]). Fatigue correlated with poorer performance on speed and accuracy ( r  > 0.30, p  < 0.05). Cognitive slowing is prevalent in neurological PCC but is scarcely captured by conventional assessments. The TAP’s computerized format with automated norming and independence from alphanumeric stimuli shows promise in improving the discriminatory ability for identifying attentional deficits in PCC patients.

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to COVID-19 (COrona VIrus Disease-2019). SARS-CoV-2 acute infection may be associated with an increased incidence of neurological manifestations such as encephalopathy and encephalomyelitis, ischemic stroke and intracerebral hemorrhage, anosmia and neuromuscular diseases. Neurological manifestations are commonly reported during the post-acute phase and are also present in Long-COVID (LCS) and post-COVID-19 syndrome (PCS). In October 2020, the German Society of Neurology (DGN, Deutsche Gesellschaft für Neurologie) published the first guideline on the neurological manifestations of COVID-19. In December 2021 this S1 guideline was revised and guidance for the care of patients with post-COVID-19 syndrome regarding neurological manifestations was added. This is an abbreviated version of the post-COVID-19 syndrome chapter of the guideline issued by the German Neurological society and published in the Guideline repository of the AWMF (Working Group of Scientific Medical Societies; Arbeitsgemeinschaft wissenschaftlicher Medizinischer Fachgesellschaften).

Cognitive impairment is the most frequent symptom reported in post-COVID-19 syndrome (PCS). Aetiology of cognitive impairment in PCS is still to be determined. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are increased in acute COVID-19. Their role as biomarkers in other neurological disorders is under debate. We analysed serum levels of NfL and GFAP as markers for neuronal and astrocytic damage in 53 patients presenting to a PCS Neurology outpatient clinic. Only individuals with self-reported cognitive complaints were included. In these individuals, cognitive complaints were further assessed by comprehensive neuropsychological assessment (NPA). Patients were categorized into subgroups of subjective cognitive decline, single domain impairment, or multi-domain impairment. Serum NfL was in normal range, however an increase of serum GFAP was detected in 4% of patients. Serum NfL and GFAP levels correlated with each other, even when adjusting for patient age (r = 0.347, p = 0.012). NPA showed deficits in 70%; 40% showing impairment in several tested domains. No significant differences were found between serum NfL- and GFAP-levels comparing patients with subjective cognitive decline, single domain impairment, or multi-domain impairment. Persistent neuronal or astrocytic damage did not correlate with cognitive impairment in PCS.

Coronavirus disease (COVID-19) patients treated in an intensive care unit (ICU) are at high risk of developing cognitive impairments of a \"post-intensive care syndrome\" (PICS). We explored whether critically ill COVID-19 and non-COVID-19 survivors differ in their post-ICU recovery course in terms of severity and affected cognitive domains. An observational prospective study was conducted in a German post-acute neurological early rehabilitation clinic. Critically ill patients with or without SARS-CoV-2 infection (at least mechanically ventilated for one week) underwent repeated standardized assessments during their subsequent inpatient rehabilitation stay. Cognitive functions (information processing speed, learning, recognition, short-term and working-memory, word fluency, flexibility) assigned to different domains (attention, memory, executive functions) were assessed as primary outcome. Secondary outcomes included mental (depression, anxiety) and physical (Barthel index, modified ranking scale) state. Out of 92 eligible patients (screened between June 2021 and August 2023), 34 were examined, and 30 were available for analysis (15 per group). Both groups were ventilated for a similar period (COVID-19 vs. Non-COVID-19: median: 48 vs. 53 days). Patients of COVID-19 group spend on average 10 days longer at ICU and developed slightly more complications, but subsequent inpatient rehabilitation was of comparable duration (median: 36.5 vs. 37 days). On the group-level both groups showed similar cognitive dysfunctions with striking impairments (normative T-scores < 41) in information processing speed, word fluency, flexibility, and recognition memory on admission. Significant gains until discharge were only revealed for information processing speed in both groups (main effect visit, mean difference [95%CI] - 7.5 [- 13.1, - 2.0]). Physical and mental state were also similarly affected in both groups on admission, but improved over time, indicating that overall recovery for higher-order cognitive functions is slowest. Interestingly, majority of patients stated correctly being still physically disabled, while a discrepancy was found between subjective and objective evaluation of cognitive health. Results suggest a substantial overlap of cognitive, mental and physical dysfunction in post-acute recovery of ICU survivors independent of SARS-CoV-2 infection which warrants further monitoring to reduce the risk of long-term burden and enable a return to previous functionality. Retrospectively registered at https://drks.de/search/de/trial/DRKS00025523 , 21.06.2021.

Patients suffering from neurological symptoms after COVID-19 vaccination (post-COVID-19 vaccination syndrome (PCVS)) have imposed an increasing challenge on medical practice, as diagnostic precision and therapeutic options are lacking. Underlying autoimmune dysfunctions, including autoantibodies, have been discussed in neurological disorders after SARS-CoV-2 infection and vaccination. Here, we describe the frequency and targets of autoantibodies against peripheral nervous system tissues in PCVS. Sera from 50 PCVS patients with peripheral neurological symptoms after COVID-19 vaccination and 35 vaccinated healthy controls were used in this study. IgG autoreactivity was measured via indirect immunofluorescence assays on mouse sciatic nerve teased fibers. The frequencies of autoantibodies were compared between groups using Fisher's exact test. Serum anti-ganglioside antibodies were measured in ganglioside blots. Autoantibody target identification was performed using immunoprecipitation coupled to mass spectrometry. Subsequent target confirmation was conducted via cell-based assays and ELISA. Compared with controls, PCVS patients had a significantly greater frequency of autoantibodies against peripheral nervous system structures (9/50(18%) vs 1/35(3%); p=0.04). Autoantibodies bound to paranodes (n=5), axons (n=4), Schmidt-Lanterman incisures (n=2) and Schwann cell nuclei (n=1). Conversely, antibodies against gangliosides were absent in PCVS patients. Target identification and subsequent confirmation revealed various subunits of neurofilaments as well as DFS-70 as autoantibody epitopes. Our data suggest that autoantibodies against nervous system tissue could be relevant in PCVS patients. Autoantibodies against neurofilaments and cell nuclei with so far non-established links to this disease spectrum should be further elucidated to determine their biomarker potential.

Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severely debilitating condition which markedly restricts activity and function of affected people. Since the beginning of the COVID-19 pandemic ME/CFS related to post-acute COVID-19 syndrome (PACS) can be diagnosed in a subset of patients presenting with persistent fatigue 6 months after a mostly mild SARS-CoV-2 infection by fulfillment of the Canadian Consensus Criteria (CCC 2003). Induction of autoimmunity after viral infection is a mechanism under intensive investigation. In patients with ME/CFS, autoantibodies against thyreoperoxidase (TPO), beta-adrenergic receptors (ß2AR), and muscarinic acetylcholine receptors (MAR) are frequently found, and there is evidence for effectiveness of immunomodulation with B cell depleting therapy, cyclophosphamide, or intravenous immunoglobulins (IVIG). Preliminary studies on the treatment of ME/CFS patients with immunoadsorption (IA), an apheresis that removes antibodies from plasma, suggest clinical improvement. However, evidence from placebo-controlled trials is currently missing. Methods In this double-blinded, randomized, sham-controlled, exploratory trial the therapeutic effect of five cycles of IA every other day in patients with ME/CFS, including patients with post-acute COVID-19 chronic fatigue syndrome (PACS-CFS), will be evaluated using the validated Chalder Fatigue Scale, a patient-reported outcome measurement. A total of 66 patients will be randomized at a 2:1 ratio: 44 patients will receive IA (active treatment group) and 22 patients will receive a sham apheresis (control group). Moreover, safety, tolerability, and the effect of IA on patient-reported outcome parameters, biomarker-related objectives, cognitive outcome measurements, and physical parameters will be assessed. Patients will be hospitalized at the clinical site from day 1 to day 10 to receive five IA treatments and medical visits. Four follow-up visits (including two visits at site and two visits via telephone call) at month 1 (day 30), 2 (day 60), 4 (day 120), and 6 (day 180; EOS, end of study visit) will take place. Discussion Although ME/CFS including PACS-CFS causes an immense individual, social, and economic burden, we lack efficient therapeutic options. The present study aims to investigate the efficacy of immunoadsorption and to contribute to the etiological understanding and establishment of diagnostic tools for ME/CFS. Trial registration Registration Number: NCT05710770 . Registered on 02 February 2023.