Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders.

Excitation/inhibition (E/I) balance plays important roles in mental disorders. Bioactive phospholipids like lysophosphatidic acid (LPA) are synthesized by the enzyme autotaxin (ATX) at cortical synapses and modulate glutamatergic transmission, and eventually alter E/I balance of cortical networks. Here, we analyzed functional consequences of altered E/I balance in 25 human subjects induced by genetic disruption of the synaptic lipid signaling modifier PRG-1, which were compared to 25 age and sex matched control subjects. Furthermore, we tested therapeutic options targeting ATX in a related mouse line. Using EEG combined with TMS in an instructed fear paradigm, neuropsychological analysis and an fMRI based episodic memory task, we found intermediate phenotypes of mental disorders in human carriers of a loss-of-function single nucleotide polymorphism of PRG-1 (PRG-1R345T/WT). Prg-1R346T/WT animals phenocopied human carriers showing increased anxiety, a depressive phenotype and lower stress resilience. Network analysis revealed that coherence and phase-amplitude coupling were altered by PRG-1 deficiency in memory related circuits in humans and mice alike. Brain oscillation phenotypes were restored by inhibtion of ATX in Prg-1 deficient mice indicating an interventional potential for mental disorders.

Ultrafast Brain MRI with Deep Learning Reconstruction for Suspected Acute Ischemic Stroke.

Background Deep learning (DL)-accelerated MRI can substantially reduce examination times. However, studies prospectively evaluating the diagnostic performance of DL-accelerated MRI reconstructions in acute suspected stroke are lacking. Purpose To investigate the interchangeability of DL-accelerated MRI with conventional MRI in patients with suspected acute ischemic stroke at 1.5 T. Materials and Methods In this prospective study, 211 participants with suspected acute stroke underwent clinically indicated MRI at 1.5 T between June 2022 and March 2023. For each participant, conventional MRI (including T1-weighted, T2-weighted, T2*-weighted, T2 fluid-attenuated inversion-recovery, and diffusion-weighted imaging; 14 minutes 18 seconds) and DL-accelerated MRI (same sequences; 3 minutes 4 seconds) were performed. The primary end point was the interchangeability between conventional and DL-accelerated MRI for acute ischemic infarction detection. Secondary end points were interchangeability regarding the affected vascular territory and clinically relevant secondary findings (eg, microbleeds, neoplasm). Three readers evaluated the overall occurrence of acute ischemic stroke, affected vascular territory, clinically relevant secondary findings, overall image quality, and diagnostic confidence. For acute ischemic lesions, size and signal intensities were assessed. The margin for interchangeability was chosen as 5%. For interrater agreement analysis and interrater reliability analysis, multirater Fleiss κ and the intraclass correlation coefficient, respectively, was determined. Results The study sample consisted of 211 participants (mean age, 65 years ± 16 [SD]); 123 male and 88 female). Acute ischemic stroke was confirmed in 79 participants. Interchangeability was demonstrated for all primary and secondary end points. No individual equivalence indexes (IEIs) exceeded the interchangeability margin of 5% (IEI, -0.002 [90% CI: -0.007, 0.004]). Almost perfect interrater agreement was observed (P > .91). DL-accelerated MRI provided higher overall image quality (P < .001) and diagnostic confidence (P < .001). The signal properties of acute ischemic infarctions were similar in both techniques and demonstrated good to excellent interrater reliability (intraclass correlation coefficient, ≥0.8). Conclusion Despite being four times faster, DL-accelerated brain MRI was interchangeable with conventional MRI for acute ischemic lesion detection. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Haller in this issue.

Spatial transcriptomics and neurofilament light chain reveal changes in lesion patterns in murine autoimmune neuroinflammation.

OBJECTIVE: Ongoing neuroaxonal damage is a major contributor to disease progression and long-term disability in multiple sclerosis. However, spatio-temporal distribution and pathophysiological mechanisms of neuroaxonal damage during acute relapses and later chronic disease stages remain poorly understood. METHODS: Here, we applied immunohistochemistry, single-molecule array, spatial transcriptomics, and microglia/axon co-cultures to gain insight into spatio-temporal neuroaxonal damage in experimental autoimmune encephalomyelitis (EAE). RESULTS: Association of spinal cord white matter lesions and blood-based neurofilament light (sNfL) levels revealed a distinct, stage-dependent anatomical pattern of neuroaxonal damage: in chronic EAE, sNfL levels were predominately associated with anterolateral lumbar lesions, whereas in early EAE sNfL showed no correlation with lesions in any anatomical location. Furthermore, neuroaxonal damage in late EAE was largely confined to white matter lesions but showed a widespread distribution in early EAE. Following this pattern of neuroaxonal damage, spatial transcriptomics revealed a widespread cyto- and chemokine response at early disease stages, whereas late EAE was characterized by a prominent glial cell accumulation in white matter lesions. These findings were corroborated by immunohistochemistry and microglia/axon co-cultures, which further revealed a strong association between CNS myeloid cell activation and neuroaxonal damage both in vivo and in vitro. INTERPRETATION: Our findings indicate that CNS myeloid cells may play a crucial role in driving neuroaxonal damage in EAE. Moreover, neuroaxonal damage can progress in a stage-dependent centripetal manner, transitioning from normal-appearing white matter to focal white matter lesions. These insights may contribute to a better understanding of neurodegeneration and elevated sNfL levels observed in multiple sclerosis patients at different disease stages.

Intensive heart rhythm monitoring to decrease ischemic stroke and systemic embolism-the Find-AF 2 study-rationale and design.

BACKGROUND: Atrial fibrillation (AF) is one of the most frequent causes of stroke. Several randomized trials have shown that prolonged monitoring increases the detection of AF, but the effect on reducing recurrent cardioembolism, ie, ischemic stroke and systemic embolism, remains unknown. We aim to evaluate whether a risk-adapted, intensified heart rhythm monitoring with consequent guideline conform treatment, which implies initiation of oral anticoagulation (OAC), leads to a reduction of recurrent cardioembolism. METHODS: Find-AF 2 is a randomized, controlled, open-label parallel multicenter trial with blinded endpoint assessment. 5,200 patients ≥ 60 years of age with symptomatic ischemic stroke within the last 30 days and without known AF will be included at 52 study centers with a specialized stroke unit in Germany. Patients without AF in an additional 24-hour Holter ECG after the qualifying event will be randomized in a 1:1 fashion to either enhanced, prolonged and intensified ECG-monitoring (intervention arm) or standard of care monitoring (control arm). In the intervention arm, patients with a high risk of underlying AF will receive continuous rhythm monitoring using an implantable cardiac monitor (ICM) whereas those without high risk of underlying AF will receive repeated 7-day Holter ECGs. The duration of rhythm monitoring within the control arm is up to the discretion of the participating centers and is allowed for up to 7 days. Patients will be followed for at least 24 months. The primary efficacy endpoint is the time until recurrent ischemic stroke or systemic embolism occur. CONCLUSIONS: The Find-AF 2 trial aims to demonstrate that enhanced, prolonged and intensified rhythm monitoring results in a more effective prevention of recurrent ischemic stroke and systemic embolism compared to usual care.

Association of Delirium Incidence with Visitation Restrictions due to COVID-19 Pandemic in Patients with Acute Cerebrovascular Disease in a Stroke-Unit Setting: A Retrospective Cohort Study.

INTRODUCTION: Hospitals around the world introduced considerable visitation restrictions to reduce risk of infection during epidemic spread of SARS-CoV2. Understanding of negative impacts of visitation restrictions on subgroups of patients may help to balance and adjust policies accordingly or introduce further measures to mitigate their impact. We aimed to investigate the association of visitation restrictions with delirium incidence in stroke-unit patients. METHODS: In a non-randomized observational design, data from 5,779 stroke-unit cases with transient ischemic attack or stroke (ischemic/hemorrhagic) admitted between January 2017 and November 2021 were compared between three groups depending on visitation policy implemented at time of admission: pandemic-associated absolute visitation restriction (n = 1,087), limited visitation policy (n = 862), and pre-pandemic visitation policy (n = 3,830). Univariate comparison and multiple logistic regression analyses were conducted to evaluate the association of delirium with visitation restrictions. RESULTS: We observed delirium incidences of 6.3% during pandemic-associated absolute visitation restriction, 5.8% with limited visitation policy, and 5.1% with pre-pandemic visitation policy (p = 0.239). In multiple logistic regression analyses adjusting for clinically relevant variables, we found the presence of any pandemic-associated visitation restriction (odds ratio [OR] 1.363, 95% confidence interval [CI]: 1.066-1.744, p = 0.014) and specifically absolute visitation restriction (OR 1.368, 95% CI: 1.016-1.843, p = 0.039) independently associated with delirium in patients with acute cerebrovascular disease. Other factors independently associated with delirium were older age, male sex, stroke versus transient ischemic attack, acute infection, history of dementia, and longer duration of hospital stay. CONCLUSION: Pandemic-associated visitation restrictions and specifically absolute visitation restrictions are associated with a higher incidence of delirium among stroke-unit patients with acute cerebrovascular disease. Benefit and harm of visitation restrictions should be carefully weighed and adjustments considered for patients otherwise at increased risk for delirium.

Sex Disparities in Re-Employment in Stroke Patients With Large Vessel Occlusion Undergoing Mechanical Thrombectomy.

BACKGROUND: Strokes in the working-age population represent a relevant share of ischemic strokes and re-employment is a major factor for well-being in these patients. Income differences by sex have been suspected a barrier for women in returning to paid work following ischemic stroke. We aim to identify predictors of (not) returning to paid work in patients with large vessel occlusion treated with mechanical thrombectomy (MT) to identify potential areas of targeted vocational rehabilitation. METHODS: From 6635 patients enrolled in the German Stroke Registry Endovascular Treatment between 2015 and 2019, data of 606 patients of the working population who survived large vessel occlusion at least 90 days past MT were compared based on employment status at day 90 follow-up. Univariate analysis, multiple logistic regression and analyses of area under the curve were performed to identify predictors of re-employment. RESULTS: We report 35.6% of patients being re-employed 3 months following MT (median age 54.0 years; 36.1% of men, 34.5% of women [P=0.722]). We identified independent negative predictors against re-employment being female sex (odds ratio [OR], 0.427 [95% CI, 0.229-0.794]; P=0.007), higher National Institutes of Health Stroke Scale (NIHSS) score 24 hours after MT (OR, 0.775 [95% CI, 0.705-0.852]; P<0.001), large vessel occlusion due to large-artery atherosclerosis (OR, 0.558 [95% CI, 0.312-0.997]; P=0.049) and longer hospital stay (OR, 0.930 [95% CI, 0.868-0.998]; P=0.043). Positive predictors favoring re-employment were excellent functional outcome (modified Rankin Scale score of 0-1) at 90 day follow-up (OR, 11.335 [95% CI, 4.864-26.415]; P<0.001) and combined treatment with intravenous thrombolysis (OR, 1.904 [95% CI, 1.046-3.466]; P=0.035). Multiple regression modeling increased predictive power of re-employment status significantly over prediction by best single functional outcome parameter (National Institutes of Health Stroke Scale 24 hours after MT ≤5; R2: 0.582 versus 0.432; area under the receiver operating characteristic curve: 0.887 versus 0.835, P<0.001). CONCLUSIONS: There is more to re-employment after MT than functional outcome alone. In particular, attention should be paid to possible systemic barriers deterring women from resuming paid work. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03356392.

Revacept, an Inhibitor of Platelet Adhesion in Symptomatic Carotid Stenosis: A Multicenter Randomized Phase II Trial.

BACKGROUND: Patients with symptomatic internal carotid artery (ICA) stenosis are at high risk of recurrent ischemic stroke and require early interventional treatment and antiplatelet therapy. Increased bleeding rates might counterbalance the periprocedural efficacy of intensified platelet inhibition. We aim to investigate, whether Revacept, a competitive antagonist of glycoprotein VI, adjunct to standard antiplatelet therapy reduces the occurrence of ischemic lesions in patients with symptomatic ICA stenosis. METHODS: International, multicenter (16 sites), 3-arm, randomized (1:1:1), double-blind, and placebo-controlled study with parallel groups, including patients with symptomatic ICA stenosis. A single infusion over 20 minutes of either placebo, 40 mg or 120 mg Revacept in addition to guideline-conform antiplatelet therapy was evaluated with regard to the exploratory efficacy end point: Number of new ischemic lesions on diffusion-weighted magnetic resonance imaging after treatment initiation. Main clinical outcome was the combined safety and efficacy end point including any stroke or death, transient ischemic attack, myocardial infarction, coronary intervention, and bleeding complications during follow-up. RESULTS: Out of 160 randomized patients, 158 patients (68±10.1 years, 24% female) received study medication (51 patients placebo, 54 patients 40 mg Revacept and 53 patients 120 mg Revacept) and were followed for 11.2±2.3 months. A total of 1.16 (95% CI, 0.88-1.53)/1.05 (95% CI, 0.78-1.42; P=0.629)/0.63 (95% CI, 0.43-0.93) new diffusion-weighted magnetic resonance imaging lesions per patient were detected in the placebo/40 mg/120 mg Revacept groups, without statistical evidence of a difference. A reduction of the combined safety and efficacy end point during the study period was observed in patients who received 120 mg (HR, 0.46 [95% CI, 0.21-0.99]; P=0.047), but not 40 mg Revacept compared with placebo (HR, 0.72 [95% CI, 0.37-1.42]; P=0.343). CONCLUSIONS: Revacept 120 mg reduced the combined safety and efficacy end point in patients with symptomatic ICA stenosis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique Identifier: NCT01645306.

Aetiology, secondary prevention strategies and outcomes of ischaemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation.

OBJECTIVE: To investigate the aetiology, subsequent preventive strategies and outcomes of stroke despite anticoagulation in patients with atrial fibrillation (AF). METHODS: We analysed consecutive patients with AF with an index imaging-proven ischaemic stroke despite vitamin K-antagonist (VKA) or direct oral anticoagulant (DOAC) treatment across 11 stroke centres. We classified stroke aetiology as: (i) competing stroke mechanism other than AF-related cardioembolism; (ii) insufficient anticoagulation (non-adherence or low anticoagulant activity measured with drug-specific assays); or, (iii) AF-related cardioembolism despite sufficient anticoagulation. We investigated subsequent preventive strategies with regard to the primary (composite of recurrent ischaemic stroke, intracranial haemorrhage, death) and secondary endpoint (recurrent ischaemic stroke) within 3 months after index stroke. RESULTS: Among 2946 patients (median age 81 years; 48% women; 43% VKA, 57% DOAC), stroke aetiology was competing mechanism in 713 patients (24%), insufficient anticoagulation in 934 (32%) and cardioembolism despite sufficient anticoagulation in 1299 (44%). We found high rates of the primary (27% of patients; completeness 91.6%) and secondary endpoint (4.6%; completeness 88.5%). Only DOAC (vs VKA) treatment after index stroke showed lower odds for both endpoints (primary: adjusted OR (aOR) (95% CI) 0.49 (0.32 to 0.73); secondary: 0.44 (0.24 to 0.80)), but not switching between different DOAC types. Adding antiplatelets showed higher odds for both endpoints (primary: aOR (95% CI) 1.99 (1.25 to 3.15); secondary: 2.66 (1.40 to 5.04)). Only few patients (1%) received left atrial appendage occlusion as additional preventive strategy. CONCLUSIONS: Stroke despite anticoagulation comprises heterogeneous aetiologies and cardioembolism despite sufficient anticoagulation is most common. While DOAC were associated with better outcomes than VKA, adding antiplatelets was linked to worse outcomes in these high-risk patients. Our findings indicate that individualised and novel preventive strategies beyond the currently available anticoagulants are needed. TRIAL REGISTRATION NUMBER: ISRCTN48292829.

Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug-resistant epilepsy.

OBJECTIVE: Adult drug-resistant epilepsy (DRE) is associated with significant morbidity. Infiltration of immune cells is observed in DRE epileptic foci; however, the relation between DRE and the peripheral immune cell compartment remains only partially understood. We aimed to investigate differences in immune cell populations, cytokines, and neurodegenerative biomarkers in the peripheral blood of subjects with epilepsy versus healthy controls, and in DRE compared to well-controlled epilepsy (WCE). METHODS: Peripheral blood mononuclear cells and serum from >120 age- and sex-matched adults suffering from focal onset epilepsy and controls were analyzed by multipanel flow cytometry, multiplex immunoassays, and ultrasensitive single molecule array. RESULTS: Using a data-driven analytical approach, we identified that CD4 T cells in the peripheral blood are present in a higher proportion in DRE patients. Moreover, we observed that the frequency of CD4 T cells expressing proinflammatory cytokines interleukin (IL)-17A, IL-22, tumor necrosis factor, interferon-γ, and granulocyte-macrophage colony-stimulating factor, but not anti-inflammatory cytokines IL-10 and IL-4, is elevated in the peripheral blood of DRE subjects compared to WCE. In parallel, we found that Th17-related circulating proinflammatory cytokines are elevated, but Th2-related cytokine IL-4 is reduced, in the serum of epilepsy and DRE subjects. As Th17 cells can exert neurotoxicity, we measured levels of serum neurofilament light chain (sNfL), a marker of neuronal injury. We found significantly elevated levels of sNfL in DRE compared to controls, especially among older individuals. SIGNIFICANCE: Our data support that DRE is associated with an expansion of the CD4 Tcell subset in the peripheral blood and with a shift toward a proinflammatory Th17/Th1 CD4 Tcell immune profile. Our results further show that pathological levels of sNfL are more frequent in DRE, supporting a potential neurodegenerative component in adult DRE. With this work, we provide evidence for novel potential inflammatory and degenerative biomarkers in DRE.

Brain Natriuretic Peptide and Discovery of Atrial Fibrillation After Stroke: A Subanalysis of the Find-AFRANDOMISED Trial.

Background and Purpose- Diagnosing paroxysmal atrial fibrillation (pAF) can be challenging after acute ischemic stroke. Enhanced and prolonged Holter-ECG monitoring (EPM) improves the detection rate but is not feasible for all patients. We hypothesized that brain natriuretic peptide (BNP) may help to identify patients with stroke at high risk for pAF to select patients for EPM more effectively. Methods- Patients with acute cerebral ischemia ≥60 years presenting in sinus rhythm and without history of AF were included into a prospective, randomized multicenter study to receive either EPM (3× 10-day Holter-ECG) or usual stroke care diagnostic work-up. BNP plasma levels were measured on randomization and 3 months thereafter. Levels were compared between patients with and without pAF detected by means of EPM or usual care. Furthermore, the number needed to screen for EPM depending on BNP cut offs was calculated. Results- A total of 398 patients were analyzed. In 373 patients (93.7%), BNP was measured at baseline and in 275 patients (69.1%) after 3 months. pAF was found in 27 patients by means of EPM and in 9 patients by means of usual care (P=0.002). Median BNP was higher in patients with pAF as compared to patients without AF in both study arms at baseline (57.8 versus 28.3 pg/mL in the EPM arm, P=0.0003; 46.2 versus 27.7 pg/mL, P=0.28 in the control arm) and after 3 months (74.9 versus 31.3 pg/mL, P=0.012 in the EPM arm, 99.3 versus 26.3 pg/mL, P=0.02 in the control arm). Applying a cut off of 100 pg/mL, the number needed to screen was reduced from 18 by usual care to 3 by EPM. Conclusions- BNP measured early after ischemic stroke identifies a subgroup of patients with stroke at increased risk for AF, in whom EPM is particularly efficacious. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01855035.

Endovascular Stroke Treatment and Risk of Intracranial Hemorrhage in Anticoagulated Patients.

Background and Purpose- We aimed to determine the safety and mortality after mechanical thrombectomy in patients taking vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). Methods- In a multicenter observational cohort study, we used multiple logistic regression analysis to evaluate associations of symptomatic intracranial hemorrhage (sICH) with VKA or DOAC prescription before thrombectomy as compared with no anticoagulation. The primary outcomes were the rate of sICH and all-cause mortality at 90 days, incorporating sensitivity analysis regarding confirmed therapeutic anticoagulation. Additionally, we performed a systematic review and meta-analysis of literature on this topic. Results- Altogether, 1932 patients were included (VKA, n=222; DOAC, n=98; no anticoagulation, n=1612); median age, 74 years (interquartile range, 62-82); 49.6% women. VKA prescription was associated with increased odds for sICH and mortality (adjusted odds ratio [aOR], 2.55 [95% CI, 1.35-4.84] and 1.64 [95% CI, 1.09-2.47]) as compared with the control group, whereas no association with DOAC intake was observed (aOR, 0.98 [95% CI, 0.29-3.35] and 1.35 [95% CI, 0.72-2.53]). Sensitivity analyses considering only patients within the confirmed therapeutic anticoagulation range did not alter the findings. A study-level meta-analysis incorporating data from 7462 patients (855 VKAs, 318 DOACs, and 6289 controls) from 15 observational cohorts corroborated these observations, yielding an increased rate of sICH in VKA patients (aOR, 1.62 [95% CI, 1.22-2.17]) but not in DOAC patients (aOR, 1.03 [95% CI, 0.60-1.80]). Conclusions- Patients taking VKA have an increased risk of sICH and mortality after mechanical thrombectomy. The lower risk of sICH associated with DOAC may also be noticeable in the acute setting. Improved selection might be advisable in VKA-treated patients. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03496064. Systematic Review and Meta-Analysis: CRD42019127464.

NfL (Neurofilament Light Chain) Levels as a Predictive Marker for Long-Term Outcome After Ischemic Stroke.

Background and Purpose- Ischemic stroke causes major disability as a consequence of neuronal loss and recurrent ischemic events. Biomarkers predicting tissue damage or stroke recurrence might be useful to guide an individualized stroke therapy. NfL (neurofilament light chain) is a promising biomarker that might be used for this purpose. Methods- We used individual data of patients with an acute ischemic stroke and clinical long term follow-up. Serum NfL (sNfL) was quantified within 24 hours after admission and after 1 year and compared with other biomarkers (GDF15 [growth differentiation factor 15], S100, NT-proBNP [N-terminal pro-B-type natriuretic peptide], ANP [atrial natriuretic peptide], and FABP [fatty acid-binding protein]). The primary end point was functional outcome after 90 days and cerebrovascular events and death (combined cardiovascular end point) within 36 months of follow-up. Results- Two hundred eleven patients (mean age, 68.7 years; SD, ±12.6; 41.2% women) with median clinical severity on the National Institutes of Health Stroke Scale (NIHSS) score of 3 (interquartile range, 1-5) and long-term follow-up with a median of 41.8 months (interquartile range, 40.0-44.5) were prospectively included. We observed a significant correlation between sNfL and NIHSS at hospital admission (r=0.234; P<0.001). sNfL levels increased with the grade of age-related white matter changes (P<0.001) and were able to predict unfavorable clinical outcome (modified Rankin Scale score, ≥2) 90 days after stroke (odds ratio [OR], 1.562; 95% CI, 1.003-2.433; P=0.048) together with NIHSS (OR, 1.303; 95% CI, 1.164-1.458; P<0.001) and age-related white matter change rating (severe; OR, 3.326; 95% CI, 1.186-9.326; P=0.022). Similarly, sNfL was valuable for the prediction of the combined cardiovascular end point (OR, 2.002; 95% CI, 1.213-3.302; P=0.007), besides NIHSS (OR, 1.110; 95% CI, 1.000-1.232; P=0.049), diabetes mellitus (OR, 2.942; 95% CI, 1.306-6.630; P=0.005), and age-related white matter change rating (severe; OR, 4.816; 95% CI, 1.206-19.229; P=0.026) after multivariate regression analysis. Kaplan-Meier analysis revealed significantly more combined cardiovascular end points (18 [14.1%] versus 38 [45.8%], log-rank test P<0.001) during long-term follow-up in patients with elevated sNfL levels. Conclusions- sNFL is a valuable biomarker for functional independence 90 days after ischemic stroke and predicts cardiovascular long-term outcome. Clinical Trial Registration- URL: http://www.isrctn.com. Unique identifier: ISRCTN 46104198.

Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis.

BACKGROUND: Monitoring neuronal injury remains one key challenge in early relapsing-remitting multiple sclerosis (RRMS) patients. Upon axonal damage, neurofilament - a major component of the neuro-axonal cytoskeleton - is released into the cerebrospinal fluid (CSF) and subsequently peripheral blood. OBJECTIVE: To investigate the relevance of serum neurofilament light chain (sNfL) for acute and chronic axonal damage in early RRMS. METHODS: sNfL levels were determined in 74 patients (63 therapy-naive) with recently diagnosed clinically isolated syndrome (CIS) or RRMS using Single Molecule Array technology. Standardized 3 T magnetic resonance imaging (MRI) was performed at baseline and 1-3 consecutive follow-ups (42 patients; range: 6-37 months). RESULTS: Baseline sNfL correlated significantly with T2 lesion volume ( r = 0.555, p < 0.0001). There was no correlation between baseline sNfL and age, Expanded Disability Status Scale (EDSS) score or other calculated MRI measures. However, T2 lesion volume increased ( r = 0.67, p < 0.0001) and brain parenchymal volume decreased more rapidly in patients with higher baseline sNfL ( r = -0.623, p = 0.0004). Gd-enhancing lesions correlated positively with sNfL levels. Initiation of disease-modifying treatment led to a significant decrease in sNfL levels. CONCLUSION: sNfL indicates acute inflammation as demonstrated by correlation with Gd+ lesions. It is a promising biomarker for neuro-axonal damage in early multiple sclerosis (MS) patients, since higher baseline sNfL levels predicted future brain atrophy within 2 years.

Treatment response to dimethyl fumarate is characterized by disproportionate CD8+ T cell reduction in MS.

BACKGROUND: The effect of dimethyl fumarate (DMF) on circulating lymphocyte subsets and their contribution as predictors of clinical efficacy have not yet been investigated in multiple sclerosis (MS). OBJECTIVE: To evaluate lymphocytes and lymphocyte subsets (analyzed 6 months after DMF start) in MS patients with and without disease activity after 1 year of treatment in a retrospective study. METHODS: Peripheral blood lymphocyte subsets were analyzed by flow cytometry. Untreated MS patients ( n = 40) were compared to those 6 months after onset of DMF treatment ( n = 51). Clinical and magnetic resonance imaging (MRI) disease activity of DMF-treated patients were assessed in the first year under treatment. RESULTS: Stable patients showed significantly lower lymphocytes, CD4+ and CD8+ T cells as well as CD19+ B cells compared to active patients under DMF treatment. Furthermore, an increased CD4/CD8 ratio ( p < 0.025) in stable patients indicated a disproportionate reduction of CD8+ T cells relative to CD4+ T cells. Reduced lymphocytes, CD8+ T cells, and CD19+ B cells 6 months after DMF start allowed prediction of the treatment response in the first year. CONCLUSION: DMF treatment response is reflected by lower circulating lymphocytes and specific lymphocyte subsets. Changes in the cellular immune profiles under DMF treatment are clinically relevant and might serve as a surrogate marker of treatment response.

[Duplex Sonography of the Brain-Supplying Arteries - Pitfalls]. / Doppler-Duplex-Sonografie der hirnversorgenden Gefäße ­ Fallstricke.

This CME article presents a structured examination of duplex sonography of the brain-supplying arteries, especially focusing on difficulties and pitfalls. Criteria for stenosis grading and common mistakes as well as anatomical and methodical characteristics are described in detail.

Stroke Caused by Vasculitis Induced by Periodontitis-Associated Oral Bacteria after Wisdom Teeth Extraction.

Invasive dental procedures, such as wisdom teeth removal, have been identified as potential triggers for vascular events due to the entry of oral bacteria into the bloodstream, leading to acute vascular inflammation and endothelial dysfunction. This study presents the case of a 27-year-old healthy male who developed ischemic stroke resulting from bacteremia after undergoing wisdom teeth extraction. Initially, the patient experienced fever and malaise, which were followed by right-sided hemiplegia. Diagnostic imaging, including a CT scan, identified a subacute infarction in the posterior crus of the left internal capsule, and MRI findings indicated inflammatory changes in the masticatory muscles. Further investigations involving biopsies of the masticatory muscles, along with blood and cerebrospinal fluid samples, confirmed bacterial meningitis with associated vasculitis. Notably, oral bacteria linked to periodontitis, including Porphyromonas gingivalis, Fusobacterium nucleatum, Tannerella forsythia, and Parvimonas micra, were found in the biopsies and microbiological analyses. To the best of our knowledge, this is the first reported case showing that bacteremia following dental procedures can lead to such severe neurological outcomes. This case underscores the importance of recognizing bacteremia-induced vasculitis in patients presenting with neurological symptoms post-dental procedures, emphasizing the broader implications of oral infections in such pathologies.

Cerebral vasculitis as a clinical manifestation of neurosarcoidosis: A scoping review.

The occurrence of cerebral vasculitis in individuals with neurosarcoidosis (NS) is considered to be rare. Although the number of relevant publications has increased in recent years, evidence is mostly limited to case reports. To obtain a better understanding of this rare and severe manifestation of disease, we carried out a scoping review on cerebral vasculitis in patients diagnosed with NS. The results of the review indicate that the diagnosis of cerebral vasculitis in patients with NS is made especially in patients with systemic sarcoidosis. However, recurrent strokes in patients with NS remains the main indicator of cerebral vasculitis. A tissue biopsy is considered the gold standard to confirm the diagnosis despite occasional false-negative results. Glucocorticoids and steroid-sparing agents are the most successful current treatments. Favorable outcomes were observed with strategies targeting TNFα and B cells. The goal of this review is to summarize the current literature and treatment options for cerebral vasculitis in patients with NS.

Long-Term Observation of SARS-CoV-2 Vaccination Response upon High Efficacy Treatment in Multiple Sclerosis-A Real-World Scenario.

Immunomodulatory and immunosuppressive therapy is needed in people with a chronic neuroinflammatory disease of the central nervous system such as multiple sclerosis (MS). Therefore, MS requires monitoring for and preventing against infectious diseases like SARS-CoV-2. Vaccination and anti-viral treatments are, in particular, recommended for elderly people and people at risk of a severe course of infection and of MS. Here, we asked whether repetitive infection or vaccination influenced responses upon receiving high efficacy treatments, namely sphingosine-1-phosphate receptor modulator (S1P) or anti-CD20 B cell antibody (anti-CD20) treatments. We performed a prospective real-world study of people with MS (pwMS) under S1P or anti-CD20 with repetitive exposure to the SARS-CoV-2 virus or vaccine. The measurement of anti-SARS-CoV-2 antibody titres was performed by two independent immunoassays after initial immunisation and after booster vaccination or infection. Other laboratory and clinical parameters were included in the analysis of influencing factors. As secondary outcomes, lymphocyte and immunoglobulin levels were observed longitudinally under intravenous and subcutaneous anti-CD20 treatment. In a long-term real-world cohort of 201 pwMS, we found that despite lymphopenia upon S1P drugs, the SARS-CoV-2 immunisation response increased both in selective and non-selective S1P (100% and 88% seroconversion, respectively), whereas those under anti-CD20 therapies merely exhibited a slight long-term increase in antibody titres (52% seroconversion). The latter was independent of immunoglobulin or total lymphocyte levels, which mostly remained stable. If the individual was immunised prior to therapy initiation, their levels of SARS-CoV-2 antibodies remained high under treatment. PwMS under non-selective S1P benefit from repetitive vaccination. The risk of an insufficient vaccination response mirrored by lower SARS-CoV-2 antibodies remains in pwMS receiving anti-CD20 treatment, even after repetitive exposure to the vaccine or virus. Due to the compromised vaccination response in CD20-depleting drugs, prompt antiviral treatment might be necessary.

Improvement of Neurovascular Imaging Using Ultra-High-Resolution Computed Tomography Angiography.

OBJECTIVE: To evaluate diagnostic image quality of ultra-high-resolution computed tomography angiography (UHR-CTA) in neurovascular imaging as compared to normal resolution CT-angiography (NR-CTA). MATERIAL AND METHODS: In this retrospective single-center study brain and neck CT-angiography was performed using an ultra-high-resolution computed tomography scanner (n = 82) or a normal resolution CT scanner (NR-CTA; n = 73). Ultra-high-resolution images were reconstructed with a 1024â€¯× 1024 matrix and a slice thickness of 0.25 mm, whereas NR-CT images were reconstructed with a 512â€¯× 512 matrix and a slice thickness of 0.5 mm. Three blinded neuroradiologists assessed overall image quality, artifacts, image noise, overall contrast and diagnostic confidence using a 4-point Likert scale. Furthermore, the visualization and delineation of supra-aortic arteries with an emphasis on the visualization of small intracerebral vessels was assessed using a cerebral vascular score, also utilizing a 4-point Likert scale. Quantitative analyses included signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), noise and the steepness of gray value transition. Radiation exposure was determined by comparison of computed tomography dose index (CTDIvol), dose length product (DLP) and mean effective dose. Interrater agreement was evaluated via determining Fleiss-Kappa. RESULTS: Ultra-high-resolution CT-angiography (UHR-CTA) yielded excellent image quality with superior quantitative (SNR: p < 0.001, CNR: p < 0.001, steepness of gray value transition: p < 0.001) and qualitative results (overall image quality: 4 (Inter quartile range (IQR) = 4-4); p < 0.001, diagnostic confidence: 4 (IQR = 4-4); p < 0.001) compared to NR-CT (overall image quality: 3 (IQR = 3-3), diagnostic confidence: 3 (IQR = 3-4)). Furthermore, UHR-CT enabled significantly superior delineation and visualization of all vascular segments, from proximal extracranial vessels to the smallest peripheral cerebral branches (e.g. , UHR-CTA PICA: 4 (3-4) vs. NR-CTA PICA: 3 (2-3); UHR-CTA P4: 4 (IQR = 3-4) vs. NR-CTA P4: 2 (IQR = 2-3); UHR-CTA M4: 4 (IQR = 4-4) vs. NR-CTA M4: 3 (IQR = 2-3); UHR-CTA A4: 4 (IQR = 3-4) vs. NR-CTA A4: 2 (IQR = 2-3); all p < 0.001). Noteworthy, a reduced mean effective dose was observed when applying UHR-CT (NR-CTA: 1.8 ± 0.3 mSv; UHR-CTA: 1.5 ± 0.5 mSv; p < 0.001). CONCLUSION: Ultra-high-resolution CT-angiography improves image quality in neurovascular imaging allowing the depiction and evaluation of small peripheral cerebral arteries. It may thus improve the detection of pathologies in small cerebrovascular lesions and the resulting diagnosis.