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

BACKGROUND: Anti-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. METHODS: Structural networks from 61 NMDAR encephalitis patients in the post-acute stage (median time from acute hospital discharge: 18 months) and 61 age- and sex-matched healthy controls (HC) were analyzed using diffusion-weighted imaging (DWI)-based probabilistic anatomically constrained tractography and volumetry of a selection of subcortical and white matter brain volumes was performed. We calculated global, modular, and nodal graph measures with special focus on default-mode network, medial temporal lobe, and hippocampus. Pathologically altered metrics were investigated regarding their potential association with clinical course, disease severity, and cognitive outcome. RESULTS: Patients 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). We found decreased left (p = 0.013) and right (p = 0.001) hippocampal volumes that were associated with hippocampal node strength (left p = 0.009; right p < 0.001). CONCLUSIONS: Focal 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.

Effectiveness of a mobile application for independent computerized cognitive training in patients with mild cognitive impairment: study protocol for the NeNaE Study, a randomized controlled trial.

BACKGROUND: Mild cognitive impairment (MCI) involves cognitive decline beyond typical age-related changes, but without significant daily activity disruption. It can encompass various cognitive domains as the causes of MCI are diverse. MCI as well as frequent comorbid neuropsychiatric conditions like depression and anxiety affect individuals' quality of life. Early interventions are essential, and computerized cognitive training (cCT) is an established treatment method. This paper presents the protocol for the NeuroNation MED Effectiveness Study, evaluating the self-administered mobile cCT intervention ("NeuroNation MED") in individuals with MCI to assess training effects on cognitive domains, health competence, neuropsychiatric symptoms, psychological well-being, and the general application usability. METHODS: This study protocol presents a single-blinded multicenter randomized controlled trial that will be carried out in six study centers in Germany and Luxembourg. We included adults with MCI (existing F06.7 ICD-10-GM diagnosis and TICS ≥ 21 and ≤ 32). The intervention group will use a mobile, multi-domain cCT ("NeuroNation MED") for 12 weeks. Meanwhile, the wait list control group will receive standard medical care or no care. The eligibility of volunteers will be determined through a telephone screening. After completion of the baseline examination, patients will be randomly assigned to one of the experimental conditions in a 2:1 ratio. In total, 286 participants will be included in this study. The primary outcome is the change of cognitive performance measured by the index score of the screening module of the Neuropsychological Assessment Battery. Secondary outcomes are changes in the Cognitive Failures Questionnaire, Hospital Anxiety and Depression Scale, Health-49, Health Literacy Questionnaire, among others. All of the primary and secondary outcomes will be assessed at baseline and after the 12-week post-allocation period. Furthermore, the intervention group will undergo an assessment of the System Usability Scale, and the training data of the NeuroNation MED application will be analyzed. DISCUSSION: This study aims to assess the effectiveness of a mobile self-administered cCT in enhancing cognitive abilities among individuals diagnosed with MCI. Should the findings confirm the effectiveness of the NeuroNation MED app, it may confer possible benefits for the care management of patients with MCI, owing to the accessibility, cost-effectiveness, and home-based setting it provides. Specifically, the cCT program could provide patients with personalized cognitive training, educational resources, and relaxation techniques, enabling participants to independently engage in cognitive training sessions at home without further supervision. TRIAL REGISTRATION: German Clinical Trials Register DRKS00025133. Registered on November 5, 2021.

Altered brain perfusion and oxygen levels relate to sleepiness and attention in post-COVID syndrome.

OBJECTIVE: Persisting neurological symptoms after COVID-19 affect up to 10% of patients and can manifest in fatigue and cognitive complaints. Based on recent evidence, we evaluated whether cerebral hemodynamic changes contribute to post-COVID syndrome (PCS). METHODS: Using resting-state functional magnetic resonance imaging, we investigated brain perfusion and oxygen level estimates in 47 patients (44.4 ± 11.6 years; F:M = 38:9) and 47 individually matched healthy control participants. Group differences were calculated using two-sample t-tests. Multivariable linear regression was used for associations of each regional perfusion and oxygen level measure with cognition and sleepiness measures. Exploratory hazard ratios were calculated for each brain metric with clinical measures. RESULTS: Patients presented with high levels of fatigue (79%) and daytime sleepiness (45%). We found widespread decreased brain oxygen levels, most evident in the white matter (false discovery rate adjusted-p-value (p-FDR) = 0.038) and cortical grey matter (p-FDR = 0.015). Brain perfusion did not differ between patients and healthy participants. However, delayed patient caudate nucleus perfusion was associated with better executive function (p-FDR = 0.008). Delayed perfusion in the cortical grey matter and hippocampus were associated with a reduced risk of daytime sleepiness (hazard ratio (HR) = 0.07, p = 0.037 and HR = 0.06, p = 0.034). Decreased putamen oxygen levels were associated with a reduced risk of poor cognitive outcome (HR = 0.22, p = 0.019). Meanwhile, lower thalamic oxygen levels were associated with a higher risk of cognitive fatigue (HR = 6.29, p = 0.017). INTERPRETATION: Our findings of lower regional brain blood oxygen levels suggest increased cerebral metabolism in PCS, which potentially holds a compensatory function. These hemodynamic changes were related to symptom severity, possibly representing metabolic adaptations.

BRAFV600E Metastatic Melanoma Journey: A Perspective from a Patient and his Oncologist.

BACKGROUND: This article is co-authored by a patient with BRAFV600E metastatic melanoma and his treating oncologist. CASE DESCRIPTION: The patient describes how he coped with his diagnosis and treatment. He details the pathway of his melanoma treatment, which has spanned over 10 years, including surgical interventions, medical treatment, and participation in clinical trials. He relates his experience of living with the disease-and the adverse effects of treatment-in the long term. The clinical perspective of his treating oncologist reviews the diagnostic process and explains how the therapeutic options were selected for and with the patient. The oncologist also addresses the integration of the patient into clinical trials involving programmed death-1 (PD-1) inhibitors and BRAF/MEK inhibitors. Challenges related to the adverse effects that occurred and the personalised treatment of the patient are also discussed. Finally, the article evaluates current advances in treatment and future therapeutic approaches. CONCLUSIONS: This case highlights the challenges of identifying which therapeutic options are most appropriate for individual patients with BRAFV600E metastatic melanoma.

About half of all people with melanoma have a BRAF^V600E gene mutation. Targeted therapies called BRAF inhibitors may be appropriate; such treatment can rapidly suppress melanoma growth and control the tumour in many patients. Immunotherapies, such as pembrolizumab, have emerged for patients with melanoma that has spread to other parts of the body. Triple combination therapy with a BRAF inhibitor, a MEK inhibitor plus pembrolizumab, can extend the therapeutic effects of BRAF/MEK inhibition, but also cause immune-related adverse events (mainly involving the gut, skin, liver, and lung). Steroids that treat these adverse events may reduce the antitumour response. This article concerns a patient who has lived with BRAF^V600E-mutant melanoma for over 10 years and illustrates the situation from the perspective of both the patient and his oncologist. The patient describes how he coped with his diagnosis and treatment challenges, and his melanoma treatment pathway, including surgical interventions, medical treatment, and participation in clinical trials. He relates his experience of living with the disease and the adverse effects of treatment. The patient's oncologist reviews the diagnostic process and explains how the therapeutic options were selected for and with the patient. The oncologist also addresses the integration of the patient into clinical trials involving programmed death-1 (PD-1) inhibitors and BRAF/MEK inhibitors. Challenges related to the adverse effects that occurred and the personalised treatment of the patient are discussed. This partnership encouraged the patient to stay on treatment, enjoy a good quality of life, care for his family, and ultimately enter complete remission.

Neuropsychiatric symptoms and metamemory across the life span: psychometric properties of the German Multifactorial Memory Questionnaire (MMQ).

OBJECTIVE: We assessed the psychometric properties, established normative data for the German Multifactorial Memory Questionnaire (MMQ), and analyzed its association with neuropsychiatric factors across the life span to provide a validated metamemory assessment for a German-speaking population. METHODS: The three MMQ scales (memory satisfaction, self-rated ability, and strategy application) were translated into German, considering cultural, linguistic, and conceptual aspects. To validate the MMQ and assess associations with neuropsychiatric factors, the Complainer Profile Identification, Geriatric Depression Scale, Beck Anxiety Inventory, Pittsburgh Sleep Quality Index, and Short-Form-Health Survey were applied in an online study in 336 healthy participants with follow-up after 8 months. RESULTS: Psychometric evaluation of the German MMQ showed normal distribution of all scales and good to excellent validity, internal consistency, and retest reliability. We provide percentiles and normative data for z-score conversion. Importantly, even subclinically elevated scores in depressiveness and anxiety were associated with decreased memory satisfaction and self-rated ability. Furthermore, although the influence of age on the German MMQ scales was minimal, effects of neuropsychiatric factors such as sleep quality, anxiety, and depressiveness on MMQ Satisfaction and Ability varied across the life span. CONCLUSIONS: Our study provides a validated German translation of the MMQ with normative data and reliability measures, including reliable change scores. We show the impact of neuropsychiatric factors on the MMQ scales across the life span and emphasize the relevance of a multifactorial approach to metamemory as a measure of individualized everyday functionality and the importance of including neuropsychiatric factors into both research and clinical assessments of metamemory.

Memory consolidation affects the interplay of place and response navigation.

Navigation through space is based on memory representations of landmarks ('place') or movement sequences ('response'). Over time, memory representations transform through consolidation. However, it is unclear how the transformation affects place and response navigation in humans. In the present study, healthy adults navigated to target locations in a virtual maze. The preference for using place and response strategies and the ability to recall place and response memories were tested after a delay of one hour (n = 31), one day (n = 30), or two weeks (n = 32). The different delays captured early-phase synaptic changes, changes after one night of sleep, and long-delay changes due to the reorganization of navigation networks. Our results show that the relative contributions of place and response navigation changed as a function of time. After a short delay of up to one day, participants preferentially used a place strategy and exhibited a high degree of visual landmark exploration. After a longer delay of two weeks, place strategy use decreased significantly. Participants now equally relied on place and response strategy use and increasingly repeated previously taken paths. Further analyses indicate that response strategy use predominantly occurred as a compensatory strategy in the absence of sufficient place memory. Over time, place memory faded before response memory. We suggest that the observed shift from place to response navigation is context-dependent since detailed landmark information, which strongly relied on hippocampal function, decayed faster than sequence information, which required less detail and depended on extra-hippocampal areas. We conclude that changes in place and response navigation likely reflect the reorganization of navigation networks during systems consolidation.

Definition of the Post-COVID syndrome using a symptom-based Post-COVID score in a prospective, multi-center, cross-sectoral cohort of the German National Pandemic Cohort Network (NAPKON).

PURPOSE: The objective examination of the Post-COVID syndrome (PCS) remains difficult due to heterogeneous definitions and clinical phenotypes. The aim of the study was to verify the functionality and correlates of a recently developed PCS score. METHODS: The PCS score was applied to the prospective, multi-center cross-sectoral cohort (in- and outpatients with SARS-CoV-2 infection) of the "National Pandemic Cohort Network (NAPKON, Germany)". Symptom assessment and patient-reported outcome measure questionnaires were analyzed at 3 and 12 months (3/12MFU) after diagnosis. Scores indicative of PCS severity were compared and correlated to demographic and clinical characteristics as well as quality of life (QoL, EQ-5D-5L). RESULTS: Six hundred three patients (mean 54.0 years, 60.6% male, 82.0% hospitalized) were included. Among those, 35.7% (215) had no and 64.3% (388) had mild, moderate, or severe PCS. PCS severity groups differed considering sex and pre-existing respiratory diseases. 3MFU PCS worsened with clinical severity of acute infection (p = .011), and number of comorbidities (p = .004). PCS severity was associated with poor QoL at the 3MFU and 12MFU (p < .001). CONCLUSION: The PCS score correlated with patients' QoL and demonstrated to be instructive for clinical characterization and stratification across health care settings. Further studies should critically address the high prevalence, clinical relevance, and the role of comorbidities. TRAIL REGISTRATION NUMBER: The cohort is registered at www. CLINICALTRIALS: gov under NCT04768998.

Cognitive decline in post-COVID-19 syndrome does not correspond with persisting neuronal or astrocytic damage.

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.

HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease.

Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement and bulbar-associated dysfunction. The presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, supports an autoimmune basis. In this study, a multicentric human leukocyte antigen (HLA) study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared with one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T-cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.

Fractal Dimension Analysis in Neurological Disorders: An Overview.

Fractal analysis has emerged as a powerful tool for characterizing irregular and complex patterns found in the nervous system. This characterization is typically applied by estimating the fractal dimension (FD), a scalar index that describes the topological complexity of the irregular components of the nervous system, both at the macroscopic and microscopic levels, that may be viewed as geometric fractals. Moreover, temporal properties of neurophysiological signals can also be interpreted as dynamic fractals. Given its sensitivity for detecting changes in brain morphology, FD has been explored as a clinically relevant marker of brain damage in several neuropsychiatric conditions as well as in normal and pathological cerebral aging. In this sense, evidence is accumulating for decreases in FD in Alzheimer's disease, frontotemporal dementia, Parkinson's disease, multiple sclerosis, and many other neurological disorders. In addition, it is becoming increasingly clear that fractal analysis in the field of clinical neurology opens the possibility of detecting structural alterations in the early stages of the disease, which highlights FD as a potential diagnostic and prognostic tool in clinical practice.

Mapping dysfunctional circuits in the frontal cortex using deep brain stimulation.

Frontal circuits play a critical role in motor, cognitive and affective processing, and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)functions remains largely elusive. We studied 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregated the frontal cortex into circuits that had become dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to frontal, ranging from interconnections with sensorimotor cortices in dystonia, the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairments in the human brain.

Characteristic functional connectome related to Post-COVID-19 syndrome.

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.

Dataset for: Autoantibody profiles in patients with immune checkpoint inhibitor-induced neurological immune-related adverse events.

The rise of cancer immunotherapy has been a milestone in clinical oncology. Above all, immune checkpoint inhibitor treatment (ICI) with monoclonal antibodies targeting programmed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has improved survival rates for an increasing number of malignancies. However, despite the clinical benefits, ICI-related autoimmunity has become a significant cause of non-relapse-related morbidity and mortality. Neurological immune-related adverse events (irAE-n) are particularly severe toxicities with a high risk for chronic illness, long-term steroid dependency, and early ICI treatment termination. While the clinical characteristics of irAE-n are well described, little is known about underlying immune mechanisms and potential biomarkers. Recently, high frequencies of neuronal autoantibodies in patients with irAE-n have been reported, however, their clinical relevance is unclear. Here, we present a dataset on neuronal autoantibody profiles in ICI-treated cancer patients with and without irAE-n, which was generated to investigate the potential role of neuronal autoantibodies in ICI-induced autoimmunity. Between September 2017 and January 2022 serum samples of 29 cancer patients with irAE-n post-ICI treatment) and 44 cancer control patients without high-grade immune-related adverse events (irAEs, n = 44 pre- and post-ICI treatment) were collected and tested for a large panel of brain-reactive and neuromuscular autoantibodies using indirect immunofluorescence and immunoblot assays. Prevalence of autoantibodies was compared between the groups and correlated with clinical characteristics such as outcome and irAE-n manifestation. These data represent the first systematic comparison of neuronal autoantibody profiles between ICI-treated cancer patients with and without irAE-n, providing valuable information for both researchers and clinicians. In the future, this dataset may be valuable for meta-analyses on the prevalence of neuronal autoantibodies in cancer patients.

Predictors of non-recovery from fatigue and cognitive deficits after COVID-19: a prospective, longitudinal, population-based study.

Background: Despite the high prevalence and major disability associated with fatigue and cognitive deficits after SARS-CoV-2 infection, little is known about long-term trajectories of these sequelae. We aimed to assess long-term trajectories of these conditions and to identify risk factors for non-recovery. Methods: We analyzed longitudinal data from the population-based COVIDOM/NAPKON-POP cohort in Germany. Participants with confirmed SARS-CoV-2 infection were assessed at least 6 months (baseline) and again at least 18 months (follow-up) after infection using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale (cutoff ≤ 30) and the Montreal Cognitive Assessment (MoCA, cutoff ≤ 25). Predictors of recovery from fatigue or cognitive deficits between assessments were identified through univariate and multivariable logistic regression models. The COVIDOM study is registered at the German registry for clinical studies (DRKS00023742) and at ClinicalTrials.gov (NCT04679584). Findings: Between 15 November 2020 and 9 May 2023, a total of 3038 participants were assessed at baseline (median 9 months after infection) and 83% responded to invitations for follow-up (median 26 months after infection). At baseline, 21% (95% confidence interval (CI) [20%, 23%]) had fatigue and 23% (95% CI [22%, 25%]) had cognitive deficits according to cutoff scores on the FACIT-Fatigue or MoCA. Participants with clinically relevant fatigue (at baseline) showed significant improvement in fatigue scores at follow-up (Hedges' g [95% CI] = 0.73 [0.60, 0.87]) and 46% (95% CI [41%, 50%]) had recovered from fatigue. Participants with cognitive deficits showed a significant improvement in cognitive scores (g [95% CI] = 1.12 [0.90, 1.33]) and 57% (95% CI [50%, 64%]) had recovered from cognitive deficits. Patients with fatigue exhibiting a higher depressive symptom burden and/or headache at baseline were significantly less likely to recover. Significant risk factors for cognitive non-recovery were male sex, older age and <12 years of school education. Importantly, SARS-CoV-2 reinfection had no significant impact on recovery from fatigue or cognitive deficits. Interpretation: Fatigue and cognitive deficits are common sequelae after SARS-CoV-2 infection. These syndromes improved over time and about half of the patients recovered within two years. The identified risk factors for non-recovery from fatigue and cognitive deficits could play an important role in shaping targeted strategies for treatment and prevention. Funding: Funded by the German Federal Ministry of Education and Research (BMBF; grant number 01KX2121) and German Research Foundation (DFG) Excellence Cluster "Position Medicine in Information".

Superficial white matter integrity in neuromyelitis optica spectrum disorder and multiple sclerosis.

Background: Superficial white matter (SWM) is a particularly vulnerable area of white matter adjacent to cerebral cortex that was shown to be a sensitive marker of disease severity in several neurological and psychiatric disorders, including multiple sclerosis (MS), but has not been studied in neuromyelitis optica spectrum disorder (NMOSD). Objective: To compare the integrity of SWM between MS patients, NMOSD patients and healthy controls, and explore the correlation of SWM integrity with cognitive performance and overall disability. Methods: Forty NMOSD patients, 48 MS patients and 52 healthy controls were included in the study. Mean diffusivity (MD) values obtained by diffusion tensor imaging were used as a measure of SWM integrity. Cognitive performance and overall disability were assessed with standardized tests. Results: Superficial white matter MD was increased in MS patients compared to healthy controls. Higher MD was associated with poorer spatial memory (most prominently in right temporal and right limbic lobe) and poorer information processing speed in MS patients. After adjusting for age, no significant differences of SWM MD were observed between NMOSD patients and healthy controls. Conclusion: Integrity of SWM is compromised in MS, but not in NMOSD, and can serve as a sensitive marker of disease severity.

Analysis of acute COVID-19 including chronic morbidity: protocol for the deep phenotyping National Pandemic Cohort Network in Germany (NAPKON-HAP).

BACKGROUND: The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic causes a high burden of acute and long-term morbidity and mortality worldwide despite global efforts in containment, prophylaxis, and therapy. With unprecedented speed, the global scientific community has generated pivotal insights into the pathogen and the host response evoked by the infection. However, deeper characterization of the pathophysiology and pathology remains a high priority to reduce morbidity and mortality of coronavirus disease 2019 (COVID-19). METHODS: NAPKON-HAP is a multi-centered prospective observational study with a long-term follow-up phase of up to 36 months post-SARS-CoV-2 infection. It constitutes a central platform for harmonized data and biospecimen for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients. RESULTS: Primary outcome measures include clinical scores and quality of life assessment captured during hospitalization and at outpatient follow-up visits to assess acute and chronic morbidity. Secondary measures include results of biomolecular and immunological investigations and assessment of organ-specific involvement during and post-COVID-19 infection. NAPKON-HAP constitutes a national platform to provide accessibility and usability of the comprehensive data and biospecimen collection to global research. CONCLUSION: NAPKON-HAP establishes a platform with standardized high-resolution data and biospecimen collection of hospitalized COVID-19 patients of different disease severities in Germany. With this study, we will add significant scientific insights and provide high-quality data to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity.

Translating spatial navigation evaluation from experimental to clinical settings: The virtual environments navigation assessment (VIENNA).

Spatial navigation abilities are frequently impaired in neurological disorders and they also decline with normal aging. Researchers and clinicians therefore need valid and easy-to-use spatial navigation assessment tools to study the impact of different neuropathologies and prevent relevant cognitive impairments from going undetected. However, current experimental paradigms rarely address which cognitive processes they recruit, often have resource-intensive setups, and usually require active navigation, e.g., using a joystick or keyboard, thus confounding cognitive performance with fine motor skills. Yet, for clinical feasibility, time-efficient paradigms are needed that are informative and easy to administer in participants with limited technical experience and diverging impairments. Here, we introduce the virtual environments navigation assessment (VIENNA), a virtual adaptation of a brief, standardized, and intuitive spatial navigation paradigm ( https://osf.io/kp4c5/ ). VIENNA is designed to assess spatial navigation without episodic memory demands, requires no interface device, and takes about 16 min to complete. We evaluated VIENNA in 79 healthy middle-aged to older participants (50-85 years) and provide evidence for its feasibility and construct validity. Tests of visuospatial and executive functions, but not episodic memory or selective attention, were identified as cognitive correlates of VIENNA, even when controlling for participant age and overall cognitive performance. Furthermore, VIENNA scores correlated with subjective navigation ability and age, but not with depressiveness, cognitive complaints, or education. The straightforward administration of VIENNA allows for its integration into routine neuropsychological assessments and enables differentiated evaluation of spatial navigation performance in patients with motor impairments and episodic memory deficits.

The T1-weighted/T2-weighted ratio as a biomarker of anti-NMDA receptor encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis rarely causes visible lesions in conventional MRI, yet advanced imaging detects extensive white matter damage. To improve prognostic capabilities, we evaluate the T1-weighted/T2-weighted (T1w/T2w) ratio, a measure of white matter integrity computable from clinical MRI sequences, in NMDAR encephalitis and examine its associations with cognitive impairment. METHODS: T1-weighted and T2-weighted MRI were acquired cross-sectionally at 3 Tesla in 53 patients with NMDAR encephalitis (81% women, mean age 29 years) and 53 matched healthy controls. Quantitative and voxel-wise group differences in T1w/T2w ratios and associations with clinical and neuropsychological outcomes were assessed. P-values were false discovery rate (FDR) adjusted where multiple tests were conducted. RESULTS: Patients with NMDAR encephalitis had significantly lower T1w/T2w ratios across normal appearing white matter (p=0.009, Hedges' g=-0.51), which was associated with worse verbal episodic memory performance (r=0.39, p=0.005, p(FDR)=0.026). White matter integrity loss was observed in the corticospinal tract, superior longitudinal fascicle, optic radiation and callosal body with medium to large effects (Cohen's d=[0.42-1.17]). In addition, patients showed decreased T1w/T2w ratios in the hippocampus (p=0.002, p(FDR)=0.005, Hedges' g=-0.62), amygdala (p=0.002, p(FDR)=0.005, Hedges' g=-0.63) and thalamus (p=0.010, p(FDR)=0.019, Hedges' g=-0.51). CONCLUSIONS: The T1w/T2w ratio detects microstructural changes in grey and white matter of patients with NMDAR encephalitis that correlate with cognitive performance. Computable from conventional clinical MRI sequences, this measure shows promise in bridging the clinico-radiological dissociation in NMDAR encephalitis and could serve as an imaging outcome measure in clinical trials.

Neuropsychological Testing in Autoimmune Encephalitis: A Scoping Review.

BACKGROUND AND OBJECTIVES: Identifying optimal methods for evaluation and monitoring of cognitive outcomes in AE is important for clinical care and research. This scoping review aimed to evaluate neuropsychological tests (NPT) that are most frequently impaired in AE cohorts to provide recommendations for a standardized NPT battery for AE outcome. METHODS: PubMed search for studies examining NPT in patients with AE was conducted on June 9, 2023. Studies were screened for inclusion/exclusion criteria as follows: at least 1 NPT, individual NPT test scores with comparison with healthy controls or normative data and neural-IgG status, total sample size ≥5, and English manuscript available. RESULTS: The search yielded 5,393 studies, of which 3,359 were screened, 107 were full text reviewed, and 32 met inclusion/exclusion criteria, anti-NMDA-R (k = 18), anti-LGI1 (k = 10), anti-GABAB-R (k = 2), anti-GAD-65 (k = 4), and anti-CASPR2 (k = 3). The cognitive domains most frequently impaired were visual and verbal episodic memory, attention/working memory, processing speed, and aspects of executive functions. DISCUSSION: Given the dearth of literature examining NPT in AE in combination with small sample sizes and methodological differences, more research in this area is needed. However, we provide recommendations for a test battery to be used in future studies, with the aim of standardizing research in this area. Based on the available literature, we recommend the use of comprehensive NPT batteries, spanning all cognitive domains. The highest yield measures may include the tests of (1) visual and verbal learning/memory, (2) basic and sustained attention, (3) processing speed, and (4) executive functions.

The Patient Perspective in Encephalitis Research.

Research on autoimmune and infectious encephalitis has made substantial progress in recent years in revealing the pathophysiology of these diseases, establishing robust diagnostic criteria, and developing promising treatment options, with a range of clinical trials currently underway. Outcome measures in studies on autoimmune and infectious encephalitis mainly relied on established and widely used tools such as the modified Rankin Scale (mRS). However, the mRS was developed to assess stroke outcome and has a strong focus on motor symptoms and the degree of dependence in daily activities. For example, approximately 80% of patients with anti-NMDA receptor encephalitis (i.e., the most common autoimmune encephalitis variant) achieve a good outcome 2 years after disease onset when evaluated using the mRS.1 In contrast to these findings, recent studies show that a majority of patients with anti-NMDA receptor encephalitis suffer from relevant and persistent cognitive impairment, despite mRS scores indicating good or very good recovery.2,3 This shows that the mRS fails to detect clinically relevant long-term symptoms in these patients. Indeed, persisting cognitive deficits with their detrimental effect on quality of life are specifically important in the frequently very young patients with encephalitis. More recently, encephalitis-specific scores have been developed, e.g., the CASE score for the clinical assessment of patients with autoimmune encephalitis.4 While this score is tailored to symptoms in autoimmune encephalitis, it has a strong focus on acute disease symptoms and is less well suited to capture long-term sequalae.