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Drug discovery is a generally inefficient and capital-intensive process. For neurodegenerative diseases (NDDs), the development of novel therapeutics is particularly urgent considering the long list of late-stage drug candidate failures. Although our knowledge on the pathogenic mechanisms driving neurodegeneration is growing, additional efforts are required to achieve a better and ultimately complete understanding of the pathophysiological underpinnings of NDDs. Beyond the etiology of NDDs being heterogeneous and multifactorial, this process is further complicated by the fact that current experimental models only partially recapitulate the major phenotypes observed in humans. In such a scenario, multi-omic approaches have the potential to accelerate the identification of new or repurposed drugs against a multitude of the underlying mechanisms driving NDDs. One major advantage for the implementation of multi-omic approaches in the drug discovery process is that these overarching tools are able to disentangle disease states and model perturbations through the comprehensive characterization of distinct molecular layers (i.e., genome, transcriptome, proteome) up to a single-cell resolution. Because of recent advances increasing their affordability and scalability, the use of omics technologies to drive drug discovery is nascent, but rapidly expanding in the neuroscience field. Combined with increasingly advanced in vitro models, which particularly benefited from the introduction of human iPSCs, multi-omics are shaping a new paradigm in drug discovery for NDDs, from disease characterization to therapeutics prediction and experimental screening. In this review, we discuss examples, main advantages and open challenges in the use of multi-omic approaches for the in vitro discovery of targets and therapies against NDDs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Carraro, Montgomery, Klimmt, Paquet, Schultze and Beyer.)

Objective: Endovascular thrombectomy (EVT) is the standard of care for acute large vessel occlusion stroke. Recently, the ANGEL-ASPECT and SELECT 2 trials showed improved outcomes in patients with acute ischemic Stroke presenting with large infarcts. The cost-effectiveness of EVT for this subpopulation of stroke patients has only been calculated using data from the previously published RESCUE-Japan LIMIT trial. It is, therefore, limited in its generalizability to an international population. With this study we primarily simulated patient-level costs to analyze the economic potential of EVT for patients with large ischemic stroke from a public health payer perspective based on the recently published data and secondarily identified determinants of cost-effectiveness., Methods: Costs and outcome of patients treated with EVT or only with the best medical care based on the recent prospective clinical trials ANGEL-ASPECT, SELECT2 and RESCUE-Japan LIMIT. A A Markov model was developed using treamtment outcomes derived from the most recent available literature. Deterministic and probabilistic sensitivity analyses addressed uncertainty., Results: Endovascular treatment resulted in an incremental gain of 1.32 QALYs per procedure with cost savings of $17,318 per patient. Lifetime costs resulted to be most sensitive to the costs of the endovascular procedure., Conclusion: EVT is a cost-saving (i.e., dominant) strategy for patients presenting with large ischemic cores defined by inclusion criteria of the recently published ANGEL-ASPECT, SELECT2, and RESCUE-Japan LIMIT trials in comparison to best medical care in our simulation. Prospective data of individual patients need to be collected to validate these results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Schwarting, Froelich, Kirschke, Mehrens, Bodden, Sepp, Reis, Dimitriadis, Ricke, Zimmer, Boeckh-Behrens and Kunz.)

Background: Recent studies have implied that ongoing intravenous thrombolysis (IVT) during endovascular treatment (ET) improves functional outcomes in patients who have undergone stroke caused by a large vessel occlusion (LVO). In this study, we investigated the effect of ongoing IVT until completion of ET on procedure duration, first-pass thrombectomy rate, and periprocedural complications., Methods: We analyzed patients from the German Stroke Registry-Endovascular Treatment dataset, collected between June 2015 and December 2021. Primary outcomes were modified Rankin Scale (mRS) score after 3 months and achievement of a Thrombolysis In Cerebral Infarction (TICI) score of 2b-3. Secondary parameters included ET duration, first-pass thrombectomy, and periprocedural complications., Results: Of the 13,082 patients in the dataset, 1,639 met the study inclusion criteria. A total of n = 317 patients (19.3%) underwent ongoing IVT until completion of ET, while IVT was completed prior to ET in 1,322 patients (80.7%). Ongoing IVT was associated with higher rates of achievement of an mRS score of 0-2 (or a back-to-baseline) after 3 months [odds ratio (OR) 1.53; 95% confidence interval (CI) 1.08-2.17]. Furthermore, ongoing IVT was predictive of achievement of a TICI score of 2b-3 (OR 1.37; 95% CI 1.03-1.83) and of first-pass thrombectomy (OR 2.07; 95% CI 1.51-2.84), while reducing the rate of peri-interventional complications (OR 0.64; 95% CI 0.44-0.94) and reducing ET duration by 24 min [β = -24.35; 95% CI -32.92-(-15.79)]., Conclusion: Our findings suggest that ongoing IVT until ET completion has a favorable impact on both clinical and angiographic outcomes, as well as on periprocedural conditions, regardless of the overall time intervals involved. Therefore, rapid ET after IVT should be sought in order to take advantage of the additive effect of ongoing IVT during ET. Future studies should consider IVT timing in the context of ET as a potential confounder and treatment target., Competing Interests: LKel has received funding for travel or speaker honoraria from Alexion, AstraZeneca, Bayer Vital, Boehringer Ingelheim, Bristol-Meyer-Squibb, Daiichi Sankyo, and Pfizer outside of this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wischmann, Pradhan, Zimmermann, Keidel, Tiedt, Dimitriadis, Liebig, Höglinger and Kellert.)

Objective: Endovascular thrombectomy is a long-established therapy for acute basilar artery occlusion (aBAO). Unlike for anterior circulation stroke, cost-effectiveness of endovascular treatment has not been evaluated and is urgently needed to calculate expected health benefits and financial rewards. The aim of this study was therefore to simulate patient-level costs, analyze the economic potential of endovascular thrombectomy in patients with acute basilar artery occlusion (aBAO), and identify major determinants of cost-effectiveness., Methods: A Markov model was developed to compare outcome and cost parameters between patients treated by endovascular thrombectomy and patients treated by best medical care, based on four recent prospective clinical trials (ATTENTION, BAOCHE, BASICS, and BEST). Treatment outcomes were derived from the most recent literature. Uncertainty was addressed by deterministic and probabilistic sensitivity analyses. Willingness to pay per QALY thresholds were set at 1x gross domestic product per capita , as recommended by the World Health Organization., Results: Endovascular treatment of acute aBAO stroke yielded an incremental gain of 1.71 quality-adjusted life-years per procedure with an incremental cost-effectiveness ratio of $7,596 per QALY. This was substantially lower than the Willingness to pay of $63,593 per QALY. Lifetime costs were most sensitive to costs of the endovascular procedure., Conclusion: Endovascular treatment is cost-effective in patients with aBAO stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schwarting, Rühling, Bodden, Schwarting, Zimmer, Mehrens, Kirschke, Kunz, Boeckh-Behrens and Froelich.)

Neural circuits are characterized as interconnecting neuron networks connected by synapses. Some kinds of gene expression and/or functional changes of neurons and synaptic connections may result in aberrant neural circuits, which has been recognized as one crucial pathological mechanism for the onset of many neurological diseases. Gradual advances in single-cell sequencing approaches with strong technological advantages, as exemplified by high throughput and increased resolution for live cells, have enabled it to assist us in understanding neuronal diversity across diverse brain regions and further transformed our knowledge of cellular building blocks of neural circuits through revealing numerous molecular signatures. Currently published transcriptomic studies have elucidated various neuronal subpopulations as well as their distribution across prefrontal cortex, hippocampus, hypothalamus, and dorsal root ganglion, etc. Better characterization of brain region-specific circuits may shed light on new pathological mechanisms involved and assist in selecting potential targets for the prevention and treatment of specific neurological disorders based on their established roles. Given diverse neuronal populations across different brain regions, we aim to give a brief sketch of current progress in understanding neuronal diversity and neural circuit complexity according to their locations. With the special focus on the application of single-cell sequencing, we thereby summarize relevant region-specific findings. Considering the importance of spatial context and connectivity in neural circuits, we also discuss a few published results obtained by spatial transcriptomics. Taken together, these single-cell sequencing data may lay a mechanistic basis for functional identification of brain circuit components, which links their molecular signatures to anatomical regions, connectivity, morphology, and physiology. Furthermore, the comprehensive characterization of neuron subtypes, their distributions, and connectivity patterns via single-cell sequencing is critical for understanding neural circuit properties and how they generate region-dependent interactions in different context., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xing, Zan and Liu.)

Background: In subarachnoid hemorrhage (SAH), titrating sedation to find a balance between wakefulness with the ability to perform valid clinical examinations on the one hand, and deep sedation to minimize secondary brain damage, on the other hand, is challenging. However, data on this topic are scarce, and current guidelines do not provide recommendations for sedation protocols in SAH., Methods: We designed a web-based, cross-sectional survey for German-speaking neurointensivists to map current standards for the indication and monitoring of sedation, duration of prolonged sedation, and biomarkers for the withdrawal of sedation., Results: Overall, 17.4% (37/213) of neurointensivists answered the questionnaire. Most of the participants were neurologists (54.1%, 20/37) and exhibited a long-standing experience in intensive care medicine (14.9 years, SD 8.3). Among indications for prolonged sedation in SAH, the control of intracranial pressure (ICP) (94.6%) and status epilepticus (91.9%) were most significant. With regard to further complications in the course of the disease, therapy refractory ICP (45.9%, 17/37) and radiographic surrogates of elevated ICP, such as parenchymal swelling (35.1%, 13/37), were the most relevant topics for experts. Regular awakening trials were performed by 62.2% of neurointensivists (23/37). All participants used clinical examination for the therapeutic monitoring of sedation depth. A total of 83.8% of neurointensivists (31/37) used methods based on electroencephalography. As a mean duration of sedation before attempting an awakening trial in patients with unfavorable biomarkers, neurointensivists suggested 4.5 days (SD 1.8) for good-grade SAH and 5.6 days (SD 2.8) for poor-grade SAH, respectively. Many experts performed cranial imaging before the definite withdrawal of sedation [84.6% (22/26)], and 63.6% (14/22) of the participants required an absence of herniation, space-occupying lesions, or global cerebral edema. The values of ICP tolerated for definite withdrawal were smaller compared to that of awakening trials (17.3 mmHg vs. 22.1 mmHg), and patients were required to stay below the threshold value for several hours (21.3 h, SD 10.7)., Conclusion: Despite the paucity of clear recommendations for sedation management in SAH in the pre-existing literature, we found some level of agreement indicating clinical efficacy for certain clinical practices. By mapping the current standard, this survey may help to identify controversial aspects in the clinical care of SAH and thereby streamline future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schmidbauer, Lanz, Maskos, Putz, Kunst and Dimitriadis.)

Introduction: Several lifestyle factors promote protection against Alzheimer's disease (AD) throughout a person's lifespan. Although such protective effects have been described for occupational cognitive requirements (OCR) in midlife, it is currently unknown whether they are conveyed by brain maintenance (BM), brain reserve (BR), or cognitive reserve (CR) or a combination of them., Methods: We systematically derived hypotheses for these resilience concepts and tested them in the population-based AgeCoDe cohort and memory clinic-based AD high-risk DELCODE study. The OCR score (OCRS) was measured using job activities based on the O*NET occupational classification system. Four sets of analyses were conducted: (1) the interaction of OCR and APOE-ε4 with regard to cognitive decline (N = 2,369, AgeCoDe), (2) association with differentially shaped retrospective trajectories before the onset of dementia of the Alzheimer's type (DAT; N = 474, AgeCoDe), (3) cross-sectional interaction of the OCR and cerebrospinal fluid (CSF) AD biomarkers and brain structural measures regarding memory function (N = 873, DELCODE), and (4) cross-sectional and longitudinal association of OCR with CSF AD biomarkers and brain structural measures (N = 873, DELCODE)., Results: Regarding (1), higher OCRS was associated with a reduced association of APOE-ε4 with cognitive decline (mean follow-up = 6.03 years), consistent with CR and BR. Regarding (2), high OCRS was associated with a later onset but subsequently stronger cognitive decline in individuals converting to DAT, consistent with CR. Regarding (3), higher OCRS was associated with a weaker association of the CSF Aβ42/40 ratio and hippocampal volume with memory function, consistent with CR. Regarding (4), OCR was not associated with the levels or changes in CSF AD biomarkers (mean follow-up = 2.61 years). We found a cross-sectional, age-independent association of OCRS with some MRI markers, but no association with 1-year-change. OCR was not associated with the intracranial volume. These results are not completely consistent with those of BR or BM., Discussion: Our results support the link between OCR and CR. Promoting and seeking complex and stimulating work conditions in midlife could therefore contribute to increased resistance to pathologies in old age and might complement prevention measures aimed at reducing pathology., Competing Interests: ME receives research funding and consulting fees from Eli Lilly and Company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kleineidam, Wolfsgruber, Weyrauch, Zulka, Forstmeier, Roeske, van den Bussche, Kaduszkiewicz, Wiese, Weyerer, Werle, Fuchs, Pentzek, Brettschneider, König, Weeg, Bickel, Luppa, Rodriguez, Freiesleben, Erdogan, Unterfeld, Peters, Spruth, Altenstein, Lohse, Priller, Fliessbach, Kobeleva, Schneider, Bartels, Schott, Wiltfang, Maier, Glanz, Incesoy, Butryn, Düzel, Buerger, Janowitz, Ewers, Rauchmann, Perneczky, Kilimann, Görß, Teipel, Laske, Munk, Spottke, Roy, Brosseron, Heneka, Ramirez, Yakupov, Scherer, Maier, Jessen, Riedel-Heller and Wagner.)

Spinal cord injury (SCI) remains one kind of devastating neurological damage, and specific molecular mechanisms involved need to be understood deeply. Currently, circular RNAs (circRNAs), as a newly discovered type of non-coding RNAs (ncRNAs), have been under active investigation. Through functional interactions with disease-associated microRNAs (miRNAs), exosome-derived circRNAs have been extensively implicated in various organ pathogenesis. Nevertheless, the functional involvement of circulating circRNAs in SCI onset, progression as well as repair remains poorly explored until now. Of note, there still lacks clinical and experimental evidence in this regard. To obtain some relevant knowledge in this field, this study was originally designed to have a general overview of differentially expressed circRNAs derived from circulating exosomes in SCI rats in comparison with the control rats. It turned out that 709 types of downregulated circRNAs and 346 kinds of upregulated circRNAs were preliminarily screened out. Functional enrichment analyses including kyoto encyclopedia of genes and genomes (KEGG) pathway and gene ontology (GO) were performed to evaluate the possible biological functions of upregulated as well as downregulated circRNAs involved in SCI. Furthermore, five types of upregulated circulating circRNAs including chr4:208359914-208362182+, chr15:20088296-20092102+, chr1:175098934- 175134845-, chr1:175099657- 175128203-, and chr1:175104454- 175134845-, and plus five kinds of downregulated circulating circRNAs including chr11:74154652- 74159524-, chr12:45412398- 45412635-, chr7:137630261- 137648924-, chr6:6280974-6281188+, and chr4:225251864-225254087+, were verified through reverse transcription-polymerase chain reaction (RT-PCR). At last, taking these differentially expressed circRNAs in the center, the circRNA-miRNA-mRNA gene interaction network was constructed to predict the possible functionalities of circRNAs in SCI through anticipating specific interactive miRNAs, giving new insights into how circRNAs contribute to this pathological process. Taken together, these findings suggest the possible involvement and functional significance of circRNAs in SCI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zan, Li, Lin and Wang.)

Background: We demonstrated experimentally that inhaled nitric oxide (iNO) dilates hypoperfused arterioles, increases tissue perfusion, and improves neurological outcome following subarachnoid hemorrhage (SAH) in mice. We performed a prospective pilot study to evaluate iNO in patients with delayed cerebral ischemia after SAH., Methods: SAH patients with delayed cerebral ischemia and hypoperfusion despite conservative treatment were included. iNO was administered at a maximum dose of 40 ppm. The response to iNO was considered positive if: cerebral artery diameter increased by 10% in digital subtraction angiography (DSA), or tissue oxygen partial pressure (PtiO 2 ) increased by > 5 mmHg, or transcranial doppler (TCD) values decreased more than 30 cm/sec, or mean transit time (MTT) decreased below 6.5 secs in CT perfusion (CTP). Patient outcome was assessed at 6 months with the modified Rankin Scale (mRS)., Results: Seven patients were enrolled between February 2013 and September 2016. Median duration of iNO administration was 23 h. The primary endpoint was reached in all patients (five out of 17 DSA examinations, 19 out of 29 PtiO 2 time points, nine out of 26 TCD examinations, three out of five CTP examinations). No adverse events necessitating the cessation of iNO were observed. At 6 months, three patients presented with a mRS score of 0, one patient each with an mRS score of 2 and 3, and two patients had died., Conclusion: Administration of iNO in SAH patients is safe. These results call for a larger prospective evaluation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fung, Z'Graggen, Jakob, Gralla, Haenggi, Rothen, Mordasini, Lensch, Söll, Terpolilli, Feiler, Oertel, Raabe, Plesnila, Takala and Beck.)

Background: Stroke in UK Biobank (UKB) is ascertained via linkages to coded administrative datasets and self-report. We studied the accuracy of these codes using genetic validation., Methods: We compiled stroke-specific and broad cerebrovascular disease (CVD) code lists (Read V2/V3, ICD-9/-10) for medical settings (hospital, death record, primary care) and self-report. Among 408,210 UKB participants, we identified all with a relevant code, creating 12 stroke definitions based on the code type and source. We performed genome-wide association studies (GWASs) for each definition, comparing summary results against the largest published stroke GWAS (MEGASTROKE), assessing genetic correlations, and replicating 32 stroke-associated loci., Results: The stroke case numbers identified varied widely from 3,976 (primary care stroke-specific codes) to 19,449 (all codes, all sources). All 12 UKB stroke definitions were significantly correlated with the MEGASTROKE summary GWAS results (rg.81-1) and each other (rg.4-1). However, Bonferroni-corrected confidence intervals were wide, suggesting limited precision of some results. Six previously reported stroke-associated loci were replicated using ≥1 UKB stroke definition., Conclusions: Stroke case numbers in UKB depend on the code source and type used, with a 5-fold difference in the maximum case-sample size. All stroke definitions are significantly genetically correlated with the largest stroke GWAS to date., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rannikmäe, Rawlik, Ferguson, Avramidis, Jiang, Pirastu, Shen, Davidson, Woodfield, Malik, Dichgans, Tenesa and Sudlow.)

Background: Leukocytes contribute to tissue damage after cerebral ischemia; however, the mechanisms underlying this process are still unclear. This study investigates the temporal and spatial relationship between vascular leukocyte recruitment and tissue damage and aims to uncover which step of the leukocyte recruitment cascade is involved in ischemic brain injury., Methods: Male wild-type, ICAM-1-deficient, anti-CD18 antibody treated, or selectin-deficient [fucusyltransferase (FucT IV/VII -/- )] mice were subjected to 60 min of middle cerebral artery occlusion (MCAo). The interaction between leukocytes and the cerebrovascular endothelium was quantified by in vivo fluorescence microscopy up to 15 h thereafter. Temporal dynamics of neuronal cell death and leukocyte migration were assessed at the same time points and in the same tissue volume by histology., Results: In wild-type mice, leukocytes started to firmly adhere to the wall of pial postcapillary venules two hours after reperfusion. Three hours later, neuronal loss started and 13 h later, leukocytes transmigrated into brain tissue. Loss of selectin function did not influence this process. Application of an anti-CD18 antibody or genetic deletion of ICAM-1, however, significantly reduced tight adhesion of leukocytes to the cerebrovascular endothelium (-60%; p < 0.01) and increased the number of viable neurons in the ischemic penumbra by 5-fold ( p < 0.01); the number of intraparenchymal leukocytes was not affected., Conclusions: Our findings suggest that ischemia triggers only a transient adhesion of leukocytes to the venous endothelium and that inhibition of this process is sufficient to partly prevent ischemic tissue damage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sienel, Kataoka, Kim, Seker and Plesnila.)

Background: Adipose-derived stem cells (ASCs) are multipotent mesenchymal stem cells characterized by their strong regenerative potential and low oxygen consumption. Macrophage migration inhibitory factor (MIF) is a multifunctional chemokine-like cytokine that is involved in tissue hypoxia. MIF is not only a major immunomodulator but also is highly expressed in adipose tissue such as subcutaneous adipose tissue of chronic non-healing wounds. In the present study, we investigated the effect of hypoxia on MIF in ASCs isolated from healthy versus inflamed adipose tissue. Methods: Human ASCs were harvested from 17 patients (11 healthy adipose tissue samples, six specimens from chronic non-healing wounds). ASCs were treated in a hypoxia chamber at <1% oxygen. ASC viability, MIF secretion as well as expression levels of MIF, its receptor CD74, hypoxia-inducible transcription factor-1α (HIF-1α) and activation of the AKT and ERK signaling pathways were analyzed. The effect of recombinant MIF on the viability of ASCs was determined. Finally, the effect of MIF on the viability and production capacity of ASCs to produce the inflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-6, and IL-1β was determined upon treatment with recombinant MIF and/or a blocking MIF antibody. Results: Hypoxic treatment inhibited proliferation of ASCs derived from healthy or chronic non-healing wounds. ASCs from healthy adipose tissue samples were characterized by a low degree of MIF secretion during hypoxic challenge. In contrast, in ASCs from adipose tissue samples of chronic non-healing wounds, secretion and expression of MIF and CD74 expression were significantly elevated under hypoxia. This was accompanied by enhanced ERK signaling, while AKT signaling was not altered. Recombinant MIF did stimulate HIF-1α expression under hypoxia as well as AKT and ERK phosphorylation, while no effect on ASC viability was observed. Recombinant MIF significantly reduced the secretion of IL-1β under hypoxia and normoxia, and neutralizing MIF-antibodies diminished TNF-α and IL-1β release in hypoxic ASCs. Conclusions: Collectively, MIF did not affect the viability of ASCs from neither healthy donor site nor chronic wounds. Our results, however, suggest that MIF has an impact on the wound environment by modulating inflammatory factors such as IL-1β., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hofmann, Soppert, Ruhl, Gousopoulos, Gerra, Storti, Tian, Brandhofer, Schweizer, Song, Lindenblatt, Pallua, Bernhagen and Kim.)

Background: The hippocampus and its subfields (HippSub) are reported to be diminished in patients with Alzheimer's disease (AD), bipolar disorder (BD), and major depressive disorder (MDD). We examined these groups vs healthy controls (HC) to reveal HippSub alterations between diseases. Methods: We segmented 3T-MRI T2-weighted hippocampal images of 67 HC, 58 BD, and MDD patients from the AFFDIS study and 137 patients from the DELCODE study assessing cognitive decline, including subjective cognitive decline (SCD), amnestic mild cognitive impairment (aMCI), and AD, via Free Surfer 6.0 to compare volumes across groups. Results: Groups differed significantly in several HippSub volumes, particularly between patients with AD and mood disorders. In comparison to HC, significant lower volumes appear in aMCI and AD groups in specific subfields. Smaller volumes in the left presubiculum are detected in aMCI and AD patients, differing from the BD group. A significant linear regression is seen between left hippocampus volume and duration since the first depressive episode. Conclusions: HippSub volume alterations were observed in AD, but not in early-onset MDD and BD, reinforcing the notion of different neural mechanisms in hippocampal degeneration. Moreover, duration since the first depressive episode was a relevant factor explaining the lower left hippocampal volumes present in groups., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hansen, Singh, Bartels, Brosseron, Buerger, Cetindag, Dobisch, Dechent, Ertl-Wagner, Fliessbach, Haynes, Heneka, Janowitz, Kilimann, Laske, Metzger, Munk, Peters, Priller, Roy, Scheffler, Schneider, Spottke, Spruth, Teipel, Tscheuschler, Vukovich, Wiltfang, Duezel, Jessen and Goya-Maldonado.)

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AL declared a shared affiliation, though no other collaboration, with several of the authors (IK, NP) to the handling Editor., (Copyright © 2021 Boltze, Aronowski, Badaut, Buckwalter, Caleo, Chopp, Dave, Didwischus, Dijkhuizen, Doeppner, Dreier, Fouad, Gelderblom, Gertz, Golubczyk, Gregson, Hamel, Hanley, Härtig, Hummel, Ikhsan, Janowski, Jolkkonen, Karuppagounder, Keep, Koerte, Kokaia, Li, Liu, Lizasoain, Ludewig, Metz, Montagne, Obenaus, Palumbo, Pearl, Perez-Pinzon, Planas, Plesnila, Raval, Rueger, Sansing, Sohrabji, Stagg, Stetler, Stowe, Sun, Taguchi, Tanter, Vay, Vemuganti, Vivien, Walczak, Wang, Xiong and Zille.)

Atherogenesis and arterial remodeling following mechanical injury are driven by inflammation and mononuclear cell infiltration. The binding of immune complexes (ICs) to immunoglobulin (Ig)-Fc gamma receptors (FcγRs) on most innate and adaptive immune cells induces a variety of inflammatory responses that promote atherogenesis. Here, we studied the role of FcγRIII in neointima formation after arterial injury in atherosclerosis-prone mice and compared the outcome and mechanism to that of FcγRIII in diet-induced "chronic" atherosclerosis. Fc γ rIII -/- /Apoe -/- and control Apoe -/- mice were subjected to wire-induced endothelial denudation of the carotid artery while on high-fat diet (HFD). Fc γ rIII deficiency mitigated neointimal plaque formation and lesional macrophage accumulation, and enhanced neointimal vascular smooth muscle cell (VSMC) numbers. This went along with a reduced expression of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1/CCL2), and vascular cell adhesion molecule-1 (VCAM-1) in the neointimal lesions. Interestingly, in a chronic model of diet-induced atherosclerosis, we unraveled a dichotomic role of FcγRIII in an early versus advanced stage of the disease. While Fc γ rIII deficiency conferred atheroprotection in the early stage, it promoted atherosclerosis in advanced stages. To this end, Fc γ rIII deficiency attenuated pro-inflammatory responses in early atherosclerosis but promoted these events in advanced stages. Analysis of the mechanism(s) underlying the athero-promoting effect of Fc γ rIII deficiency in late-stage atherosclerosis revealed increased serum levels of anti-oxidized-LDL immunoglobulins IgG2c and IgG2b. This was paralleled by enhanced lesional accumulation of IgGs without affecting levels of complement-activated products C5a or C5ar1, FcγRII, and FcγRIV. Moreover, Fc γ rIII -deficient macrophages expressed more Fc γ rII , Tnf-α , and Il-1β mRNA when exposed to IgG1 or oxLDL-IgG1 ICs in vitro , and peripheral CD4+ and CD8+ T-cell levels were altered. Collectively, our data suggest that deficiency of activating Fc γ RIII limits neointima formation after arterial injury in atherosclerosis-prone mice as well as early stage chronic atherosclerosis, but augments late-stage atherosclerosis suggesting a dual role of FcγRIII in atherogenic inflammation., (Copyright © 2020 Asare, Koehncke, Selle, Simsekyilmaz, Jankowski, Shagdarsuren, Gessner, Bernhagen and Shagdarsuren.)

The study of shared variation in gray matter morphology may define neurodegenerative diseases beyond what can be detected from the isolated assessment of regional brain volumes. We, therefore, aimed to (1) identify SCNs (structural covariance networks) that discriminate between Alzheimer's disease (AD) patients and healthy controls (HC), (2) investigate their diagnostic accuracy in comparison and above established markers, and (3) determine if they are associated with cognitive abilities. We applied a random forest algorithm to identify discriminating networks from a set of 20 SCNs. The algorithm was trained on a main sample of 104 AD patients and 104 age-matched HC and was then validated in an independent sample of 28 AD patients and 28 controls from another center. Only two of the 20 SCNs contributed significantly to the discrimination between AD and controls. These were a temporal and a secondary somatosensory SCN. Their diagnostic accuracy was 74% in the original cohort and 80% in the independent samples. The diagnostic accuracy of SCNs was comparable with that of conventional volumetric MRI markers including whole brain volume and hippocampal volume. SCN did not significantly increase diagnostic accuracy beyond that of conventional MRI markers. We found the temporal SCN to be associated with verbal memory at baseline. No other associations with cognitive functions were seen. SCNs failed to predict the course of cognitive decline over an average of 18 months. We conclude that SCNs have diagnostic potential, but the diagnostic information gain beyond conventional MRI markers is limited., (Copyright © 2020 Wagner, Duering, Gesierich, Enzinger, Ropele, Dal-Bianco, Mayer, Schmidt and Koini.)

Parameters of water diffusion in white matter derived from diffusion-weighted imaging (DWI), such as fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AD, and RD), and more recently, peak width of skeletonized mean diffusivity (PSMD), have been proposed as potential markers of normal and pathological brain ageing. However, their relative evolution over the entire adult lifespan in healthy individuals remains partly unknown during early and late adulthood, and particularly for the PSMD index. Here, we gathered and analyzed cross-sectional diffusion tensor imaging (DTI) data from 10 population-based cohort studies in order to establish the time course of white matter water diffusion phenotypes from post-adolescence to late adulthood. DTI data were obtained from a total of 20,005 individuals aged 18.1 to 92.6 years and analyzed with the same pipeline for computing skeletonized DTI metrics from DTI maps. For each individual, MD, AD, RD, and FA mean values were computed over their FA volume skeleton, PSMD being calculated as the 90% peak width of the MD values distribution across the FA skeleton. Mean values of each DTI metric were found to strongly vary across cohorts, most likely due to major differences in DWI acquisition protocols as well as pre-processing and DTI model fitting. However, age effects on each DTI metric were found to be highly consistent across cohorts. RD, MD, and AD variations with age exhibited the same U-shape pattern, first slowly decreasing during post-adolescence until the age of 30, 40, and 50 years, respectively, then progressively increasing until late life. FA showed a reverse profile, initially increasing then continuously decreasing, slowly until the 70s, then sharply declining thereafter. By contrast, PSMD constantly increased, first slowly until the 60s, then more sharply. These results demonstrate that, in the general population, age affects PSMD in a manner different from that of other DTI metrics. The constant increase in PSMD throughout the entire adult life, including during post-adolescence, indicates that PSMD could be an early marker of the ageing process., (Copyright © 2020 Beaudet, Tsuchida, Petit, Tzourio, Caspers, Schreiber, Pausova, Patel, Paus, Schmidt, Pirpamer, Sachdev, Brodaty, Kochan, Trollor, Wen, Armstrong, Deary, Bastin, Wardlaw, Munõz Maniega, Witte, Villringer, Duering, Debette and Mazoyer.)

Epidemiological studies suggest that pharmacological reduction of systemic hypertension lowers incidence and severity of stroke. However, whether the reduction of blood pressure per se or the compounds used to reduce hypertension are responsible for this effect received little attention. In the current study we therefore aimed to investigate whether Aliskiren, a renin-inhibitor used to treat arterial hypertension, may improve outcome in a mouse model of ischemic stroke when applied centrally and in a dose not affecting blood pressure. Male C57BL/6 mice received 0.6, 2.0, or 6.0 μg Aliskiren or vehicle by intracerebroventricular injection as a pre-treatment and were then subjected to 60 min of middle cerebral artery occlusion (MCAo). Infarct volume, brain edema formation, mortality, antioxidant effects, and functional outcome were assessed up to seven days after MCAo. Central administration of Aliskiren (0.6 or 2.0 μg) had no effect on systemic blood pressure but significantly reduced infarct volume and brain edema formation, blunted mortality, and improved neurological outcome up to 1 week after MCAo. Due to the central and prophylactic administration of the compound, we cannot make any conclusions about the potency of Aliskiren for acute stroke treatment, however, our study clearly demonstrates, that in addition to lowering blood pressure Aliskiren seems to have a direct neuroprotective effect. Hence, renin-inhibitors may be an effective addition to prophylactic treatment regimens in stroke patients.

Objective: In CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), white matter hyperintensities (WMH) are considered to result from hypoperfusion. We hypothesized that in fact the burden of WMH results from the combination of several regional populations of WMH with different mechanisms and clinical consequences. Methods: To identify regional WMH populations, we used a 4-step approach. First, we used an unsupervised principal component algorithm to determine, without a priori knowledge, the main sources of variation of the global spatial pattern of WMH. Thereafter, to determine whether these sources are likely to include relevant information regarding regional populations of WMH, we tested their relationships with: (1) MRI markers of the disease; (2) the clinical severity assessed by the Mattis Dementia Rating scale (MDRS) (cognitive outcome) and the modified Rankin's score (disability outcome). Finally, through careful interpretation of all the results, we tried to identify different regional populations of WMH. Results: The unsupervised principal component algorithm identified 3 main sources of variation of the global spatial pattern of WMH, which showed significant and sometime inverse relationships with MRI markers and clinical scores. The models predicting clinical severity based on these sources outperformed those evaluating WMH by their volume (MDRS, coefficient of determination of 39.0 vs. 35.3%, p = 0.01; modified Rankin's score, 43.7 vs. 38.1%, p = 0.001). By carefully interpreting the visual aspect of these sources as well as their relationships with MRI markers and clinical severity, we found strong arguments supporting the existence of different regional populations of WMH. For instance, in multivariate analyses, larger extents of WMH in anterior temporal poles and superior frontal gyri were associated with better outcomes, while larger extents of WMH in pyramidal tracts were associated with worse outcomes, which could not be explained if WMH in these different areas shared the same mechanisms. Conclusion: The results of the present study support the hypothesis that the whole extent of WMH results from a combination of different regional populations of WMH, some of which are associated, for yet undetermined reasons, with milder forms of the disease.

Neuroinflammation, the inflammatory response in the central nervous system (CNS), is a major determinant of neuronal function and survival during aging and disease progression. Microglia, as the resident tissue-macrophages of the brain, provide constant support to surrounding neurons in healthy brain. Upon any stress signal (such as trauma, ischemia, inflammation) they are one of the first cells to react. Local and/or peripheral signals determine microglia stress response, which can vary within a continuum of states from beneficial to detrimental for neuronal survival, and can be shaped by aging and previous insults. In this review, we discuss the roles of microglia upon an ischemic or traumatic injury, and give our perspective how aging may contribute to microglia behavior in the injured brain. We speculate that a deeper understanding of specific microglia identities will pave the way to develop more potent therapeutics to treat the diseases of aging brain.

Traumatic brain injury (TBI) results in immediate brain damage that is caused by the mechanical impact and is non-reversible. This initiates a cascade of delayed processes which cause additional-secondary-brain damage. Among these secondary mechanisms, the inflammatory response is believed to play an important role, mediating actions that can have both protective and detrimental effects on the progression of secondary brain damage. Histological data generated extensive information; however, this is only a snapshot of processes that are, in fact, very dynamic. In contrast, in vivo microscopy provides detailed insight into the temporal and spatial patterns of cellular dynamics. In this review, we aim to summarize data which was generated by in vivo microscopy, specifically investigating the immune response following brain trauma, and its potential effects on secondary brain damage.