PURPOSE:To evaluate the structural and microvascular chorioretinal characteristics in patients with Parkinson's disease (PD) and to investigate their association with the severity of disability in PD. PATIENTS AND METHODS:This prospective study included 35 patients with PD and 30 healthy, age- and sex-matched control subjects. All participants underwent both optical coherence tomography (OCT) and OCT angiography (OCTA) with enhanced depth imaging (EDI). Outcome measures included: Best corrected visual acuity (BCVA), superficial capillary plexus vessel density (VD), perfusion density (PFD), foveal avascular zone area (FAZ), central macular thickness (CMT), and subfoveal choroidal thickness (SFCT). The severity of the patients' disability was assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III). RESULTS:Compared to control subjects, PD patients showed significantly lower macular VD (16.5 ± 2.7 vs. 18.0 ± 1.3 mm/mm2, p = 0.03), lower macular PFD (39.5 ± 7.0 % vs 43.6 ± 2.6 %, p = 0.03) and higher SFCT (297 ± 69 vs. 246 ± 56, p = 0.002). The MDS-UPDRS-III showed a significant inverse correlation with BCVA and SFCT. No correlation was observed between PD duration and study measures. CONCLUSIONS:This study found lower macular perfusion density and increased choroidal thickness in patients with Parkinson's disease compared to healthy controls, suggesting altered retinal vascular status in PD. Additionally, better visual acuity and greater subfoveal choroidal thickness were associated with better clinical performance. These findings indicate a potential association between OCT and OCT-A metrics and disease characteristics in PD.

Abstract Parkinson’s disease (PD) affects an estimated 6.4 million men and 5.3 million women worldwide, and still lacks a validated peripheral biomarker. Brain tissue is inaccessible in living patients, making peripheral blood an attractive alternative, but existing studies have profiled immune cells almost exclusively as static, resting-state snapshots that cannot reveal how those cells function under challenge. A longitudinal design, following patients over time, or applying a controlled stimulus to reveal functional differences invisible at rest, offers a more sensitive window onto disease-associated dysfunction, and sex, despite differential PD incidence and progression, is rarely treated as a primary variable. Here, using ex vivo PMA/ionomycin stimulation as a controlled functional challenge, we profiled 195k PBMCs from 84 samples of 14 PD patients and 14 controls by single-cell RNA sequencing across an activation time course (0h, 2h, 4h), stratified by sex throughout. Sex explained more transcriptional variance than disease status, and male and female PD patients showed largely divergent responses at rest that converged, by peak activation, on a discrete CD8+ effector memory T cell subpopulation (Tem-CD8). This subpopulation showed an exhaustion-consistent programme, coinciding with a failure to resolve AP-1 induction and a reduction in inferred intercellular communication. The PD peripheral immune phenotype is therefore better characterised as a activation-dependent response than a fixed resting-state signature, identifying Tem-CD8 exhaustion as a disease-associated, sex-convergent candidate for further study.

Serum neurofilament light and heavy chains (sNfL and sNfH) have been assessed as neuronal markers for amyotrophic lateral sclerosis (ALS) and dementias. Whereas sNfL has robust literature, systematic studies on sNfH are lacking. Here, we aimed to assess the diagnostic value of sNfH in comparison to sNfL in a broad range of neurodegenerative disorders. We measured with immunoassays sNfH and sNfL in patients recruited in the multicenter German Frontotemporal Lobar Degeneration (FTLD) Consortium (n = 340) and in a single-center German cohort (n = 290). We assessed the diagnostic accuracy of serum biomarkers for ALS and dementia subtypes and their relationship with cognitive impairment. sNfH and sNfL were significantly increased in ALS (n = 90) vs. controls (n = 109) and ALS mimics (n = 56, p < 0.001), with sNfL showing higher discriminative accuracy (AUC = 0.94–0.95) than sNfH (AUC = 0.87–0.88). sNfH/sNfL ratio did not improve the diagnostic performance. Both markers were elevated in patients with dementia (n = 289) vs. controls (p < 0.001). sNfL was higher in behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA) and Creutzfeldt-Jakob disease (CJD) than in Alzheimer’s disease (AD), whereas sNfH was similar in AD, PPA and bvFTD. sNfL, but not sNfH, was correlated with cognitive impairment at baseline and cognitive decline at follow-up in AD and bvFTD. sNfH and sNfL are elevated in motoneuron and dementia disorders. sNfH showed good discriminative accuracy for ALS, which was slightly lower than that of sNfL. sNfL, but not sNfH, showed prognostic value for assessing cognitive decline in dementia.

IntroductionDiagnosis of frontotemporal lobar degeneration (FTLD) is complicated by high heterogeneity within diagnostic groups and overlap between them. Using an unsupervised machine learning technique this study aimed to increase understanding of neuropsychological profiles in the spectrum of FTLD syndromes and to assess the consistency of these neuropsychological profiles with diagnostic criteria.MethodsData from the German FTLD Consortium (FTLD-c) including behavioral variant of frontotemporal dementia (bvFTD), primary progressive aphasia (PPA) syndromes, i.e., semantic variant (svPPA), and non-fluent variant (nfvPPA), healthy controls, and amnestic Alzheimer's disease (AD), and logopenic variant (lvPPA) was used. K-means clustering was applied on neuropsychological and behavioral data. Analysis was repeated for varying cluster numbers (k = 2–9). Resulting clusters were inspected on the correspondence with current diagnostic groups and neuropsychological profiles of the clusters were explored.ResultsThe results indicated that, based on neuropsychological profiles, particularly homogeneous clusters emerged for healthy controls, svPPA and bvFTD. In contrast, amnestic AD did not separate well from other diagnostic groups, and nfvPPA and lvPPA clustered together. Inspecting the neuropsychological profiles of the clusters showed that segregation of bvFTD from other patient groups was most supported by companion-rated questionnaires focused on behavior. Patients with svPPA showed impairment in both language and verbal memory tasks. LvPPA and nfvPPA showed impairment in processing speed as well as short term and working memory.DiscussionUsing clustering this study provides insight into data-driven grouping of participants with FTLD based on neuropsychological deep-phenotyping. Whereas our approach confirmed svPPA and bvFTD to have comparatively homogeneous neuropsychological profiles, results suggest that the non-fluent PPA syndromes–lvPPA and nfvPPA–are difficult to segregate clinically, at least with the tests applied in our cohort. Our findings may suggest the need for further specification of clinical diagnostic criteria for these diseases.

Background: B-cell-depleting therapies are increasingly being used to treat autoimmune diseases. Although thousands of patients are and have been treated with these agents, the data are not yet strong enough to identify rare side effects with certainty.Methods: We report the case of a patient undergoing ocrelizumab therapy for relapsing multiple sclerosis who developed a severe limbic syndrome.Results: Autoimmune pathogenesis was initially suspected, with worsening on immunosuppressive therapy. Later, after diagnosis of an enterovirus infection, treatment with ribavirin and favipiravir in combination with intravenous immunoglobulins was initiated. After 4 weeks of therapy, the patient's clinical condition had stabilized with residual cognitive deficits.Conclusion: Diagnosis and treatment of enterovirus infections remain challenging, especially in patients receiving immunosuppressive therapy.

Multiple sclerosis (MS) is a disease of the central nervous system, which is reflected in impaired transmission of impulses due to damage to the myelin layer. In addition to the visual evoked potentials, the vestibular evoked myogenic potentials (VEMPs) are increasingly considered for diagnosis. Due to a low signal-to-noise ratio, several hundred stimulus responses are usually averaged in order to determine the amplitude and latencies from these curves. However, this averaging procedure also filters out information that, if taken into account, could provide further insights into the course of the disease.16 young patients with MS and an EDSS score of 1.4 ± 0.6 were compared with 92 healthy subjects of the same age. Amplitude, latency, AR and five new parameters from the analysis were used as parameters from the tactile evoked oVEMPs.The total n10 amplitude and the n10 amplitude on the left side showed relevant differences though not reaching statistical significance. In contrast, the n10 amplitude on the right side and the LSD parameter were not significantly different. All n10 latencies and the AR as well as all parameters from the novelty analysis were significantly different.On the one hand, the present study confirms already known changes in the registration of oVEMPs in patients with MS compared to healthy subjects and, on the other hand, the new parameters have the potential to better describe the current state of the disease and to provide detailed information about the current state of myelination or the site of pathophysiological processes within the CNS.

Accurate diagnosis and monitoring of neurodegenerative diseases require reliable biomarkers. Cerebrospinal fluid (CSF) proteins are promising candidates for reflecting brain pathology; however, their diagnostic utility may be compromised by natural variability between individuals, weakening their association with disease. Here, we measured the levels of 69 pre-selected proteins in cerebrospinal fluid using antibody-based suspension bead array technology in a multi-disease cohort of 499 individuals with neurodegenerative disorders including Alzheimer’s disease (AD), behavioral variant frontotemporal dementia, primary progressive aphasias, amyotrophic lateral sclerosis (ALS), corticobasal syndrome, primary supranuclear palsy, along with healthy controls. We identify significant inter-individual variability in overall CSF levels of brain-derived proteins, which could not be attributed to specific disease associations. Using linear modelling, we show that adjusting for median CSF levels of brain-derived proteins increases the diagnostic accuracy of proteins previously identified as altered in CSF in the context of neurodegenerative disorders. We further demonstrate a simplified approach for the adjustment using pairs of correlated proteins with opposite alteration in the diseases. With this approach, the proteins adjust for each other and further increase the biomarker performance through additive effect. When comparing the diseases, two proteins—neurofilament medium and myelin basic protein—showed increased levels in ALS compared to other diseases, and neurogranin showed a specific increase in AD. Several other proteins showed similar trends across the studied diseases, indicating that these proteins likely reflect shared processes related to neurodegeneration. Overall, our findings suggest that accounting for inter-individual variability is crucial in future studies to improve the identification and performance of relevant biomarkers. Importantly, we highlight the need for multi-disease studies to identify disease-specific biomarkers.

ZusammenfassungDie Multiple Sklerose ist eine Erkrankung des zentralen Nervensystems, die sich in der gestörten Reizweiterleitung durch Schädigung der Myelinschicht widerspiegelt. Neben den visuell evozierten Potenzialen sind es immer mehr auch die vestibulär evozierten myogenen Potenziale (VEMPs), die zur Befundung mitbetrachtet werden. Aufgrund eines geringen Signal-Rausch-Abstandes werden üblicherweise einige 100 Reizantworten gemittelt, um aus diesen Kurven Amplitudenhöhe und Latenzen zu bestimmen. Dieses Verfahren filtert jedoch Informationen aus der Messung heraus, welche weitere Erkenntnisse über den Krankheitszustand liefern könnten.16 junge Patienten mit MS und einem EDSS-Score von 1,4±0,6 wurden mit 92 gesunden Probanden gleichen Alters verglichen. Als Parameter wurden aus den taktil ausgelösten oVEMPs die n10-Amplitude, die n10-Latenz, das AR sowie 5 neue Parameter aus der neuen Analysemethode herangezogen.Die n10-Amplitude gesamt sowie die n10-Amplitude links waren grenzwertig signifikant unterschiedlich. Demgegenüber waren die n10-Amplitude rechts und der LSD-Parameter nicht signifikant unterschiedlich. Alle n10-Latenzen und das AR sowie alle Parameter aus der neuen Analyse waren signifikant unterschiedlich zwischen den Gruppen.Die vorliegende Studie bestätigt die zum einen schon bekannten Veränderungen in der Registrierung von oVEMPs bei Patienten mit MS gegenüber gesunden Probanden, und zum anderen haben die neuen Parameter das Potenzial, den aktuellen Krankheitszustand besser zu beschreiben und detaillierte Informationen über den aktuellen Zustand der Myelinisierung bzw. die Lokalisierung der pathophysiologischen Prozesse im ZNS zu geben.

BACKGROUND:Several studies have evaluated sex discrepancies in the prehospital management of patients with acute stroke. This systematic review and meta-analysis aims to summarize reported knowledge about sex differences in dispatch center and emergency medical service management. It proposes a roadmap of questions and the next necessary steps to ensure equitable prehospital stroke care. METHODS:We conducted a systematic review and meta-analysis, using a random-effects model with inverse weighting. PubMed, CINAHL, EMBASE, and EMCARE were searched for studies investigating sex differences in the prehospital management of patients with suspected and acute stroke. The main outcome was the relative risk (RR) for receiving a correct prehospital stroke diagnosis. Additional outcomes are related to prehospital management and time metrics. RESULTS:Sixteen studies were included, comprising 571 024 male patients and 622 764 female patients. No relevant risk of bias was detected. Female patients were less often correctly identified as stroke suspects than male patients (RR, 0.92 [95% CI, 0.89-0.96]; I2=73%). No differences were observed in the number receiving a dispatch code stroke (RR, 0.95 [95% CI, 0.88-1.02]; I2=96%), prenotification to hospital by emergency medical service (RR, 0.98 [95% CI, 0.96-1.00]; I2=92%), or conveyance to a stroke center (RR, 0.99 [95% CI, 0.79-1.24]; I2=82%). There was no difference in mean time from emergency call to hospital door (mean difference, 1.12 [95% CI, -0.64 to 2.89] minutes; I2=96%). No conclusion could be drawn for outcomes of on-site clinical management, emergency medical service-to-hospital team interaction, and most of the time metrics due to a lack of data. CONCLUSIONS:This analysis indicates sex differences in the prehospital recognition of acute stroke. However, significant heterogeneity and a lack of data for most steps of prehospital care also highlight the urgent need for high-quality studies to systematically investigate prehospital management disparity between female and male patients with suspected acute stroke. REGISTRATION:URL: https://crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42023442997.

BACKGROUND:Immune induction under B-cell depletion is complex and far from being fully understood. METHODS:We investigated clinical and immunological responses after dual homologous mRNA vaccination with BNT162b2 and after booster vaccination or infection in 14 B-cell depleted patients with inflammatory central nervous system disease in comparison to 28 healthy controls. Spike-specific IgG were determined using ELISA and neutralizing activity by surrogate assay. Reactive T cells were flow-cytometrically analyzed after spike-specific and polyclonal stimulation. Reactogenicity was self-reported using a questionnaire. RESULTS:Vaccination was well tolerated, with slightly more systemic events reported by patients. Spike-specific antibodies were induced in all controls, but only 43% of patients with significantly lower IgG levels and reduced neutralizing capacity (p < 0.0001). In contrast, spike-reactive T cells were induced in both groups with similar CD4 and higher CD8 T-cell levels in patients. Functional characterization of spike-reactive T cells revealed equally high CTLA-4 expression in both groups, but higher proportions of polyfunctional, triple-cytokine expressing CD4 and CD8 T cells in patients especially after the third immunization. Three patients experienced mild breakthrough infections after second vaccination. CONCLUSIONS:Despite limited ability of B-cell depleted patients to mount a humoral immune response after multiple doses of SARS-CoV-2 mRNA vaccination, the vaccine-induced T-cell response is robust, which may have implications for protection against severe disease.

BACKGROUND:Disconjugate eye movements are essential for depth perception in frontal-eyed species, but their underlying neural substrates are largely unknown. Lesions in the midbrain can cause disconjugate eye movements. While vertically disconjugate eye movements have been linked to defective visuo-vestibular integration, the pathophysiology and neuroanatomy of horizontally disconjugate eye movements remains elusive. METHODS:A patient with a solitary focal midbrain lesion was examined using detailed clinical ocular motor assessments, binocular videooculography and diffusion-weighted MRI, which was co-registered to a high-resolution cytoarchitectonic MR-atlas. RESULTS:The patient exhibited both vertically and horizontally disconjugate eye alignment and nystagmus. Binocular videooculography showed a strong correlation of vertical and horizontal oscillations during fixation but not in darkness. Oscillation intensities and waveforms were modulated by fixation, illumination, and gaze position, suggesting shared visual- and vestibular-related mechanisms. The lesion was mapped to a functionally ill-defined area of the dorsal midbrain, adjacent to the posterior commissure and sparing nuclei with known roles in vertical gaze control. CONCLUSION:A circumscribed region in the dorsal midbrain appears to be a key node for disconjugate eye movements in both vertical and horizontal planes. Lesioning this area produces a unique ocular motor syndrome mirroring hallmarks of developmental strabismus and nystagmus. Further circuit-level studies could offer pivotal insights into shared pathomechanisms of acquired and developmental disorders affecting eye alignment.

Background: Treatment on Mobile Stroke Units (MSU) improves outcome for patients with acute ischemic stroke, however MSU effectiveness relies on accuracy of field dispatch. We aimed at collecting representative data on dispatch infrastructure, methods of stroke identification at the dispatcher level, operation rules and accuracy of dispatcher impression relevant to MSU operations worldwide. Methods: A survey of the PREhospital Stroke Treatment Organization (PRESTO) was conducted in 2020 to include all operational MSU clinical services worldwide. Twenty of 23 MSU services (87%) on four continents responded and participated. We assessed modes of dispatch, level of dispatcher training, numbers of and reasons for dispatches, frequency of MSU cancellation before arrival at scene and diagnoses of patients with MSU management. Results: All 20 participating MSUs reported dispatching from EMS dispatch centers. Fourteen sites also reported responding to alerts from EMS following patient evaluation. With the exception of 2 MSUs, all reported initial dispatcher training for stroke recognition, but only 6 (30%) performed regular training. Median number of dispatches per year was 325 ranging from 119 to 2174. In addition to dispatches for suspected stroke, 8 (40%) were dispatched to cardiac arrest and 13 (65%) for altered level of consciousness runs. One MSU responded to other dispatch call types including seizure, syncope, headache, sick person, and other, if the call information yielded a suspicion of possible stroke diagnosis. A median of 41% of deployments were cancelled en route. Stroke was excluded in 48% of patients assessed on scene. Eighteen percent of assessed patients were diagnosed with cerebral ischemia within 4.5 hours. Conclusions: Allocating specialized resources such as MSUs to the most clinically appropriate calls is key to their efficacy and their ability to result in improved patient outcomes. Improving dispatcher recognition of stroke can potentially be ameliorated by local team education and routine feedback.

BACKGROUND:Cerebral microbleeds (CMBs) are markers of underlying hemorrhage-prone cerebral small vessel disease detected on MRI. They are associated with a heightened risk of stroke and cognitive decline. The prevalence of CMBs among Egyptian patients with ischemic stroke is not well studied. Our aim was to detect the prevalence of CMBs and associated risk factors among Egyptian patients with ischemic stroke. METHODS:A prospective, cross-sectional, single-center study of consecutive patients with ischemic stroke. Patients were recruited between January 2021 and January 2022 at the Assiut University Hospital in the south of Egypt. Patients with known bleeding diathesis were excluded. All participants underwent full neurological assessment, urgent laboratory investigations, and MRI with T2* sequence. RESULTS:The study included 404 patients, 191 (47.3%) of them were females. The mean age of the study population was 61 ± 1 years, and the mean NIHSS on admission was 12 ± 5. The prevalence of CMB was 26.5%, of whom 6.5% were young adults (age ≤45 years). CMBs were detected in 34.6% of patients with stroke caused by large artery atherosclerosis, 28.0% with small vessel disease stroke subtype, 25.2% with stroke of undetermined cause, and in 12.1% with cardioembolic stroke. History of AF, hypertension, dyslipidemia, Fazekas score >2, dual antiplatelet use, combined antiplatelet with anticoagulant treatment, and thrombolytic therapy remained independently associated with CMBs following multivariable regression analyses. CONCLUSION:The high number of identified CMBs needs to inform subsequent therapeutic management of these patients. We are unable to determine whether the association between CMBs and antithrombotic use is a causal relationship or rather confounded by indication for these treatments in our observational study. To understand more about the underlying cause of this finding, more studies are needed.

Progressive supranuclear palsy (PSP) is an atypical Parkinsonian syndrome characterized initially by falls and eye movement impairment. This multimodal imaging study aimed at eliciting structural and functional disease-specific brain alterations. T1-weighted and resting-state functional MRI were applied in multi-centric cohorts of PSP and matched healthy controls. Midbrain, cerebellum, and cerebellar peduncles showed severely low gray/white matter volume, whereas thinner cortical gray matter was observed in cingulate cortex, medial and temporal gyri, and insula. Eigenvector centrality analyses revealed regionally specific alterations. Multivariate pattern recognition classified patients correctly based on gray and white matter segmentations with up to 98% accuracy. Highest accuracies were obtained when restricting feature selection to the midbrain. Eigenvector centrality indices yielded an accuracy around 70% in this comparison; however, this result did not reach significance. In sum, the study reveals multimodal, widespread brain changes in addition to the well-known midbrain atrophy in PSP. Alterations in brain structure seem to be superior to eigenvector centrality parameters, in particular for prediction with machine learning approaches.

AbstractBehavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing.

BACKGROUND AND PURPOSE:To simulate patient-level costs, analyze the economic potential of telemedicine-based mobile stroke units for acute prehospital stroke care, and identify major determinants of cost-effectiveness, based on two recent prospective trials from the United States and Germany. METHODS:A Markov decision model was developed to simulate lifetime costs and outcomes of mobile stroke unit. The model compares diagnostic and therapeutic pathways of ischemic stroke, hemorrhagic stroke, and stroke mimic patients by conventional care or by mobile stroke units. The treatment outcomes were derived from the B_PROUD and the BEST-mobile stroke unit trials and further input parameters were derived from recent literature. Uncertainty was addressed by deterministic and probabilistic sensitivity analyses. A lifetime horizon based on the US healthcare system was adopted to evaluate different cost thresholds for mobile stroke unit and the resulting cost-effectiveness. Willingness-to-pay thresholds were set at 1x and 3x gross domestic product per capita, as recommended by the World Health Organization. RESULTS:In the base case scenario, mobile stroke unit care yielded an incremental gain of 0.591 quality-adjusted life years per dispatch. Mobile stroke unit was highly cost-effective up to a maximum average cost of 43,067 US dollars per patient. Sensitivity analyses revealed that MSU cost-effectiveness is mainly affected by reduction of long-term disability costs. Also, among other parameters, the rate of stroke mimics patients diagnosed by MSU plays an important role. CONCLUSION:This study demonstrated that mobile stroke unit can possibly be operated on an excellent level of cost-effectiveness in urban areas in North America with number of stroke mimic patients and long-term stroke survivor costs as major determinants of lifetime cost-effectiveness.

Objective: Apheresis treatment (AT) is an established standard of treatment in various neurological autoimmune diseases. Since not all patients equally benefit from AT, we saw the need to investigate the effect of different clinical, paraclinical and technical-apparative factors on the clinical outcome. Additionally, we wanted to find out whether patients who improved due to AT continue to be clinically stable under B-cell depletion (BCD). Methods: We screened all patients (n = 358) with neurological diseases who received AT at the Medical center of the University of the Saarland in the past 20 years. Different factors (e.g., age, sex, duration until onset of AT, type of AT, number of cycles, csf parameters) were analyzed retrospectively. Clinical disability was measured using the modified Rankin scale (mRS), visual acuity and the Expanded Disability Status Scale (EDSS). Results: 335 patients, categorized into 11 different autoimmune diagnosis groups, received a total of 2669 treatment cycles and showed a statistically significant improvement in mRS with AT (p < 0.001). Patients in American Society for Apheresis (ASFA) categories I (p = 0.013) and II (p = 0.035) showed a significantly greater benefit under AT than those in category III. The clinical outcome was better with shorter duration until AT onset, more cycles of AT, and more plasma volume exchanged and the presence of an autoimmune antibody. Patients who initially profited had a significantly more stable course of the disease after 1-Year-BCD (p = 0.039). Discussion: In the present study, we were able to identify various significant factors influencing the outcome of patients due to AT. Furthermore, we could show that patients with a response to AT can benefit from BCD followup therapy.

IntroductionActivation of NLRP3-containing inflammasome, which is responsible for IL-1β maturation, has been shown to contribute to Alzheimer’s disease (AD)-associated pathogenesis in both APP- and tau-transgenic mice. However, effects of NLRP3 on pericytes and subsequent cerebrovascular pathology in AD remain unknown.MethodsNLRP3-deficient and wild-type AD animal models were generated by crossing human P301S tau-transgenic mice and Nlrp3 knockout mice. AD-associated neuroinflammation, tauopathy, vasculature and pericyte coverage in the brain were investigated using immunohistological and molecular biological methods. To investigate how NLRP3 regulates pericyte activation and survival, pericytes from the brains of Nlrp3 knockout and wild-type mice were cultured, treated with IL-1β and H2O2 at different concentrations and analyzed by confocal microscopy and flow cytometry after staining with fluorescently labelled phalloidin, annexin-V and PDGFRβ antibody.ResultsDeficiency of NLRP3 (1) reduced Iba-1, GFAP and AT8 antibody-immunoreactive phosphorylated tau-positive cells, without significantly altering transcription of inflammatory genes, (2) preserved cerebral vasculature and pericyte coverage and up-regulated Osteopontin gene transcription, and (3) improved cognitive function in tau-transgenic mice. In cell culture, NLRP3 deficiency prevented pericyte apoptosis. Treatment with IL-1β or H2O2 increased the expression of PDGFRβ in NLRP3-deficient pericytes, but decreased it in NLRP3 wild-type pericytes in a dose-dependent manner.DiscussionInhibition of NLRP3 can promote pericyte survival, improve cerebrovascular function, and attenuate AD pathology in the brain of tau-transgenic mice. Our study supports NLRP3 as a novel therapeutic target for Alzheimer’s patients.