Cerebral amyloid angiopathy decades after red blood cell transfusions: a report of two cases from a prospective cohort.

BACKGROUND AND PURPOSE: Patients who underwent red blood cell (RBC) transfusion from donors who later developed multiple spontaneous intracerebral hemorrhages (ICHs) have recently been identified to have increased risk of ICH themselves. This increased risk of ICH was hypothesized to be related to iatrogenic cerebral amyloid angiopathy (iCAA) transmission. Two cases are presented who had RBC transfusion as an infant and presented with CAA at a relatively young age decades later. METHOD: Cases were identified by prospectively asking all patients at our CAA outpatient clinic (November 2023 to January 2024) about a medical history with RBC transfusion or history with a high likelihood for RBC transfusion (e.g., hemolytic disease, trauma with massive hemorrhage). Eligible patients were all diagnosed with CAA, CAA with concomitant hypertensive arteriopathy or iCAA, and without hereditary CAA. RESULTS: Between November 2023 and January 2024, 2/35 (6%, 95% confidence interval 2%-19%) outpatient clinic patients had a history of RBC transfusion and none had a high likelihood medical history. The cases presented at age 47 and 57 and had already developed severe CAA. CONCLUSIONS: Red blood cell transfusion might be a possible mechanism for iCAA; however, further prospective data collection and experimental evidence concerning blood transmission of amyloid-ß are needed.

SERS determination and multivariate classification of antibiotics in chicken meat using gold nanoparticle-decorated electrospun PVA nanofibers.

The fabrication of SERS substrate by gold nanoparticle-decorated polyvinyl alcohol electrospun nanofibers which has been used to detect trace sensing of two widely used poultry antibiotics doxycycline hydrochloride and enrofloxacin is demonstrated. The performance of the backscattered Raman signals from the proposed SERS substrate has been initially evaluated with two standard Raman active compounds namely malachite green and rhodamine-6G. The limit of detection of the proposed substrate is estimated to be 7.32 nM. Following this, the usability of the proposed SERS substrate has been demonstrated through the detection of the aforementioned antibiotics in chicken meat samples. The presence of antibiotics in chicken meat sample has been validated with the standard analytical tool of liquid chromatography-mass spectrometry and the results were compared with the proposed sensing technique. Further, principal component analysis has been performed to classify the antibiotics that are present in the field-collected meat samples.

Voltage-gated nanofluidic devices for protein capture, concentration, and release.

A nanofluidic device with spatially, non-uniformly distributed gate electrodes is reported. In this nanofluidic architecture, multiple nanochannels connect microfluidic reservoirs for the formation of a planar, hybrid microfluidic-nanofluidic device. The gate electrodes are individually addressable, fluidically isolated, and enable a non-uniform electric field distribution within the nanochannels permitting the capture of proteins and a local increase in their concentration. The removal of the gate potential allows the model protein, bovine serum albumin, to move away from the electrodes after concentration at the electrodes for the release of the captured protein. A maximum increase in the protein concentration of nearly an order of magnitude was observed as evaluated by fluorescence intensity.

Effect of retinol in the vitrification medium on viability of vitrified ovine preantral follicles and expression of key developmental and apoptosis related genes.

BACKGROUND: Vitrification increases the production of reactive oxygen species (ROS) and the antioxidants in the vitrification solution may be beneficial by reducing excessive ROS production. OBJECTIVE: To evaluate the effect of retinol supplementation in vitrification solution on viability, apoptosis and development-related gene expression in vitrified sheep preantral follicles. MATERIALS AND METHODS: Preantral follicles were isolated and randomly assigned into one of five groups: Group1, control fresh preantral follicles; Group 2, vitrification treatment; Group 3, vitrification + 2 µM retinol; Group 4, vitrification + 5 µM retinol; Group 5, vitrification + 10 µM retinol. Preantral follicles were placed in vitrification solutions and then plunged into liquid nitrogen (-196°C). After a week, the follicles were thawed and analyzed for follicular viability by trypan blue exclusion method and for gene expression. RESULTS: Vitrification with 5 µM retinol positively affected viability in comparison with vitrification without retinol (P < 0.05). There was no significant difference in viability among the Group 1, Group 2, Group 3 and Group 5. Expression of apoptotic genes BAX and Casp 3 were higher in the vitrified group, and vitrification with 5 µM retinol (Group 4) is comparable to the control fresh. Expressions of other apoptosis-related genes (i.e., BCL2L1, BAD and BAK) showed significant difference between the control fresh group and the vitrification group with 5 µM retinol. Expression of Annexin5 was also significantly different among various groups. The expression of development competence genes GDF-9 and BMP-15 were higher (P < 0.05) in the Group vitrified with 5 µM retinol. CONCLUSION: The supplementation of 5 µM retinol in vitrification solution was beneficial for the vitrification of ovine preantral follicles.

Effect of retinol as antioxidant on the post-thaw viability and the expression of apoptosis and developmental competence-related genes of vitrified preantral follicles in buffalo (Bubalus bubalis).

The present study evaluated the effect of supplementation of retinol in the vitrification solution on the viability, apoptosis and development-related gene expression in vitrified buffalo preantral follicles. Preantral follicles isolated from cortical slices of ovaries were randomly assigned into three groups: Group1-Control fresh preantral follicles; Group 2-Vitrification treatment (Vitrification solution 1 (VS1) -TCM-199 + 25 mM HEPES + Foetal bovine serum (FBS) 10%, Ethylene glycol (EG): 10%, Dimethyl sulphoxide (DMSO): 10%, Sucrose-0.3 M for 4 min; VS2- TCM-199 + 25 mM HEPES + FBS10%, EG:25%, DMSO: 25%, Sucrose:0.3 M for 45 s); Group3-vitrification treatment +5 µM of Retinol. Preantral follicles were placed in corresponding vitrification medium and plunged into liquid nitrogen (-196°C). After a week, the follicles were thawed and analysed for follicular viability and gene expression. There was no significant difference in the viability rates among the Group 1(Fresh preantral follicles) (91.46 ± 2.39%), Group 2 (89.59 ± 2.46%) and Group 3 (87.19 ± 4.05%). There was a significantly (p < .05) higher mRNA expression of BCL2L1, GDF-9 and BMP-15 in the vitrification + retinol group compared with the control group. There was a significantly (p < .05) higher expression of Caspase-3 and Annexin-5 in the vitrification group and Vitrification + retinol group compared with control group of follicles. It is concluded that the supplementation of 5 µM of Retinol in Vitrification solution was an efficient vitrification procedure for the vitrification of buffalo preantral follicles.

Machine learning identifies "rsfMRI epilepsy networks" in temporal lobe epilepsy.

OBJECTIVES: Experimental models have provided compelling evidence for the existence of neural networks in temporal lobe epilepsy (TLE). To identify and validate the possible existence of resting-state "epilepsy networks," we used machine learning methods on resting-state functional magnetic resonance imaging (rsfMRI) data from 42 individuals with TLE. METHODS: Probabilistic independent component analysis (PICA) was applied to rsfMRI data from 132 subjects (42 TLE patients + 90 healthy controls) and 88 independent components (ICs) were obtained following standard procedures. Elastic net-selected features were used as inputs to support vector machine (SVM). The strengths of the top 10 networks were correlated with clinical features to obtain "rsfMRI epilepsy networks." RESULTS: SVM could classify individuals with epilepsy with 97.5% accuracy (sensitivity = 100%, specificity = 94.4%). Ten networks with the highest ranking were found in the frontal, perisylvian, cingulo-insular, posterior-quadrant, thalamic, cerebello-thalamic, and temporo-thalamic regions. The posterior-quadrant, cerebello-thalamic, thalamic, medial-visual, and perisylvian networks revealed significant correlation (r > 0.40) with age at onset of seizures, the frequency of seizures, duration of illness, and a number of anti-epileptic drugs. CONCLUSIONS: IC-derived rsfMRI networks contain epilepsy-related networks and machine learning methods are useful in identifying these networks in vivo. Increased network strength with disease progression in these "rsfMRI epilepsy networks" could reflect epileptogenesis in TLE. KEY POINTS: • ICA of resting-state fMRI carries disease-specific information about epilepsy. • Machine learning can classify these components with 97.5% accuracy. • "Subject-specific epilepsy networks" could quantify "epileptogenesis" in vivo.

Evaluation after Orthotopic Heart Transplant: What the Radiologist Should Know.

Orthotopic heart transplant (OHT) is the treatment of choice for end-stage heart disease. As OHT use continues and postoperative survival increases, multimodality imaging evaluation of the transplanted heart will continue to increase. Although some of the imaging is performed and interpreted by cardiologists, a substantial proportion of images are read by radiologists. Because there is little to no consensus on a systematic approach to patients after OHT, radiologists must become familiar with common normal and abnormal posttreatment imaging features. Intrinsic transplant-related complications may be categorized on the basis of time elapsed since transplant into early (0-30 days), intermediate (1-12 months), and late (>12 months) stages. Although there can be some overlap between stages, it remains helpful to consider the time elapsed since surgery, because some complications are more common at certain stages. Recognition of differing OHT surgical techniques and their respective postoperative imaging features helps to avoid image misinterpretation. Expected early postoperative findings include small pneumothoraces, pleural effusions, pneumomediastinum, pneumopericardium, postoperative atelectasis, and an enlarged cardiac silhouette. Early postoperative complications also can include sternal dehiscence and various postoperative infections. The radiologist's role in the evaluation of allograft failure and rejection, endomyocardial biopsy complications, cardiac allograft vasculopathy, and posttransplant malignancy is highlighted. Because clinical manifestations of disease may be delayed in transplant recipients, radiologists often recognize postoperative complications on the basis of imaging and may be the first to suggest a specific diagnosis and thus positively affect patient outcomes. Online supplemental material is available for this article. ©RSNA, 2019.

Surface dependent enhancement in water vapor permeation through nanochannels.

Selective permeation of water vapor over liquid phase water through hydrophobic conduits finds broad use in separation processes, including desalination and membrane distillation. The tangential momentum accommodation coefficient (TMAC), a fundamental parameter that dictates momentum changes to a molecule colliding with a wall remains unknown for water vapor at room temperature and pressure conditions. Here, a nanofluidic platform with tunable hydrophobic regions that selectively barricaded flow of liquid water was patterned within glass nanochannels. The surface functionalization with an alkyltrichlorosilane led to either a fluoride or a methyl terminal group generating partially hydrophobic regions along the length of the nanochannels. Differential osmotic pressure solutions on either side of the hydrophobic region cause an isothermal evaporation-condensation process, which drives net water vapor transport from higher to lower vapor pressure solution, similar to osmotic distillation. Water vapor transport under such conditions for the 80 nm deep nanochannels was in the transitional regime with the Knudsen number ∼O(1). The TMAC was estimated experimentally to be of the order of 10-4-10-3 for both the hydrophobic coatings leading to a near-elastic collision of H2O molecules with the nanochannel walls. Use of the low TMAC surfaces was evaluated in two proof-of-concept technology demonstrations: (1) osmotic distillation using hyper-saline (brine) 3 M Utica shale flowback water as both the feed and draw and (2) separation of trace amounts of toluene and chloroform from water at high flux and selectivity. The results reported here likely provide new insights in designing hydrophilic-hydrophobic junctions for nanoscale liquid/vapor fluid transport with enhanced flux and selectivity.

Cation Dependent Surface Charge Regulation in Gated Nanofluidic Devices.

Surface charge governs nanoscale aqueous electrolyte transport, both in engineered analytical systems and in biological entities such as ion channels and ion pumps as a function of ion type and concentration. Embedded electrodes in a nanofluidic channel, isolated from the fluid in the channel by a dielectric layer, act as active, tunable gates to systematically modify local surface charge density at the interface between the nanochannel surface and the aqueous electrolyte solution, causing significant changes in measured nanochannel conductance. A systematic comparison of transport of monovalent electrolytes [potassium chloride (KCl), sodium chloride (NaCl)], 2:1 electrolytes [magnesium chloride (MgCl2), calcium chloride (CaCl2)], and electrolyte mixtures (KCl + CaCl2) through a gated nanofluidic device was performed. Ion-surface interactions between divalent Ca2+ and Mg2+ ions and the nanochannel walls reduced the native surface charge density by up to ∼4-5 times compared to the monovalent cations. In electrolyte mixtures, Ca2+ was the dominating cation with nanochannel conductance independent of KCl concentration. Systematic changes in local electrostatic surface state induced by the gate electrode are impacted by the divalent cation-surface interactions, limiting modulation of the local surface potential by the gate electrode and resulting in cation dependent nanoscale ion transport as seen through conductance measurements and numerical models.

Gold nanorod embedded reduction responsive block copolymer micelle-triggered drug delivery combined with photothermal ablation for targeted cancer therapy.

BACKGROUND: Gold nanorods, by virtue of surface plasmon resonance, convert incident light energy (NIR) into heat energy which induces hyperthermia. We designed unique, multifunctional, gold nanorod embedded block copolymer micelle loaded with GW627368X for targeted drug delivery and photothermal therapy. METHODS: Glutathione responsive diblock co-polymer was synthesized by RAFT process forming self-assembled micelle on gold nanorods prepared by seed mediated method and GW627368X was loaded on to the reduction responsive gold nanorod embedded micelle. Photothermal therapy was administered using cwNIR laser (808nm; 4W/cm2). Efficacy of nanoformulated GW627368X, photothermal therapy and combination of both were evaluated in vitro and in vivo. RESULTS: In response to photothermal treatment, cells undergo regulated, patterned cell death by necroptosis. Combining GW627368X with photothermal treatment using single nanoparticle enhanced therapeutic outcome. In addition, these nanoparticles are effective X-ray CT contrast agents, thus, can help in monitoring treatment. CONCLUSION: Reduction responsive nanorod embedded micelle containing folic acid and lipoic acid when treated on cervical cancer cells or tumour bearing mice, aggregate in and around cancer cells. Due to high glutathione concentration, micelles degrade releasing drug which binds surface receptors inducing apoptosis. When incident with 808nm cwNIR lasers, gold nanorods bring about photothermal effect leading to hyperthermic cell death by necroptosis. Combination of the two modalities enhances therapeutic efficacy by inducing both forms of cell death. GENERAL SIGNIFICANCE: Our proposed treatment strategy achieves photothermal therapy and targeted drug delivery simultaneously. It can prove useful in overcoming general toxicities associated with chemotherapeutics and intrinsic/acquired resistance to chemo and radiotherapy.

A three-state nanofluidic field effect switch.

We report a three-state nanofluidic field effect switch in an asymmetrically gated device with a forward (positive), off (zero), and a reverse (negative) current state for tunable control of ionic transport by systematically controlling the gate potential. The embedded gate electrode allows for modulation of the ionic current through the 16 nm deep channels as a function of electrolyte concentration and gate electrode location for a fixed streamwise potential.

Rethinking composite end points in clinical trials: insights from patients and trialists.

BACKGROUND: Many clinical trials use composite end points to reduce sample size, but the relative importance of each individual end point within the composite may differ between patients and researchers. METHODS AND RESULTS: We asked 785 cardiovascular patients and 164 clinical trial authors to assign 25 "spending weights" across 5 common adverse events comprising composite end points in cardiovascular trials: death, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. We then calculated end point ratios for each participant's ratings of each nonfatal end point relative to death. Whereas patients assigned an average weight of 5 to death, equal or greater weight was assigned to myocardial infarction (mean ratio, 1.12) and stroke (ratio, 1.08). In contrast, clinical trialists were much more concerned about death (average weight, 8) than myocardial infarction (ratio, 0.63) or stroke (ratio, 0.53). Both patients and trialists considered revascularization (ratio, 0.48 and 0.20, respectively) and hospitalization (ratio, 0.28 and 0.13, respectively) as substantially less severe than death. Differences between patient and trialist end point weights persisted after adjustment for demographic and clinical characteristics (P<0.001 for all comparisons). CONCLUSIONS: Patients and clinical trialists did not weigh individual components of a composite end point equally. Whereas trialists are most concerned about avoiding death, patients place equal or greater importance on reducing myocardial infarction or stroke. Both groups considered revascularization and hospitalization as substantially less severe. These findings suggest that equal weights in a composite clinical end point do not accurately reflect the preferences of either patients or trialists.

Effect of surface modification on interfacial nanobubble morphology and contact line tension.

Past research has confirmed the existence of surface nanobubbles on various hydrophobic substrates (static contact angle >90°) when imaged in air-equilibrated water. Additionally, the use of solvent exchange techniques (based on the difference in saturation levels of air in various solvents) also introduced surface nanobubbles on hydrophilic substrates (static contact angle <90°). In this work, tapping mode atomic force microscopy was used to image interfacial nanobubbles formed on bulk polycarbonate (static contact angle of 81.1°), bromo-terminated silica (BTS; static contact angle of 85.5°), and fluoro-terminated silica (FTS; static contact angle of 105.3°) surfaces when immersed in air-equilibrated water without solvent exchange. Nanobubbles formed on the above three substrates were characterized on the basis of Laplace pressure, bubble density, and contact line tension. Results reported here show that (1) the Laplace pressures of all nanobubbles formed on both BTS and polycarbonate were an order of magnitude higher than those of FTS, (2) the nanobubble number density per unit area decreased with an increase in substrate contact angle, and (3) the contact line tension of the nanobubbles was calculated to be positive for both BTS and polycarbonate (lateral radius, Rs < 50 nm for all nanobubbles), and negative for FTS (Rs > 50 nm for all nanobubbles). The nanobubble morphology and distribution before and after using the solvent exchange method (ethanol-water), on the bulk polycarbonate substrate was also characterized. Analysis for these polycarbonate surface nanobubbles showed that both the Laplace pressure and nanobubble density reduced by ≈98% after ethanol-water exchange, accompanied by a flip in the magnitude of contact line tension from positive (0.19 nN) to negative (-0.11 nN).

Incremental utility of iodine-123 meta-iodobenzylguanidine imaging beyond established heart failure risk models.

BACKGROUND: Nuclear myocardial imaging with iodine-123 meta-iodobenzylguanidine ((123)I-mIBG) is approved for risk stratification of patients with systolic heart failure (HF). Whether (123)I-mIBG imaging provides incremental prognostic utility beyond established risk models remains unclear. METHODS AND RESULTS: In a multicenter study, 961 patients with moderate systolic HF underwent (123)I-mIBG imaging and were followed for cardiac death, progressive HF, or life-threatening arrhythmias over 2 years. We constructed 4 multivariable models, using variables from each of 4 published HF risk models, and patient-level scores were calculated both before and after adding the heart-to-mediastinum ratio (H/M) from (123)I-mIBG imaging. Incremental utility was evaluated by calculating integrated discrimination improvement (IDI), which quantifies the increase in probability of experiencing the primary end point after adding H/M to each model. The composite end point occurred in 25% of patients. After adding H/M, absolute IDI ranged from 2.1% to 3.0%, representing 33%-59% relative improvements in risk stratification. Of note, hazard ratios for H/M were remarkably similar between risk models (0.40-0.44 for predicting the composite end point, 0.10-0.18 for mortality; all P < .001). CONCLUSIONS: Despite notable differences in predictor variables, patient populations, and analytic techniques from which each model was initially derived, adding (123)I-mIBG data to HF risk models consistently identified patients at lower risk of experiencing adverse events.

Quantitative electroencephalography in cerebral amyloid angiopathy.

OBJECTIVE: We investigated whether quantitative electroencephalography (qEEG) correlates with cognition and cortical superficial siderosis (cSS) in cerebral amyloid angiopathy. METHODS: We included patients with sporadic (sCAA) and hereditary Dutch-type CAA (D-CAA). Spectral measures and the phase lag index (PLI) were analyzed on qEEG. Cognition was assessed with the MoCA and cSS presence was scored on 3T-MRI. Linear regression analyses were performed to investigate these qEEG measures and cognition. Independent samples T-tests were used to analyze the qEEG measure differences between participants with and without cSS. RESULTS: We included 92 participants (44 D-CAA; 48 sCAA). A lower average peak frequency (ß[95 %CI] = 0.986[0.252-1.721]; P = 0.009) and a higher spectral ratio (ß[95 %CI] = -0.918[-1.761--0.075]; P = 0.033) on qEEG correlated with a lower MoCA score, irrespective of a history of symptomatic intracerebral hemorrhage (sICH). The PLI showed no correlation to the MoCA. qEEG slowing was not different in those with or without cSS. CONCLUSIONS: Spectral qEEG (but not PLI) reflects cognitive performance in patients with CAA with and without a history of sICH. We found no association between qEEG slowing and cSS. SIGNIFICANCE: qEEG could be a valuable biomarker, especially in challenging cognitive testing situations in CAA, and a potential predictive tool in future studies.

Sensitivity of the Boston criteria version 2.0 in Dutch-type hereditary cerebral amyloid angiopathy.

BACKGROUND AND AIM: The revised Boston criteria v2.0 for cerebral amyloid angiopathy (CAA) add two radiological markers to the existing criteria: severe visible perivascular spaces in the centrum semiovale and white matter hyperintensities (WMHs) in a multispot pattern. This study aims to determine the sensitivity of the updated criteria in mutation carriers with Dutch-type hereditary CAA (D-CAA) in an early and later disease stage. METHODS: In this cross-sectional study, we included presymptomatic and symptomatic D-CAA mutation carriers from our prospective natural history study (AURORA) at the Leiden University Medical Center between 2018 and 2021. 3-Tesla scans were assessed for CAA-related magnetic resonance imaging (MRI) markers. We compared the sensitivity of the Boston criteria v2.0 to the previously used modified Boston criteria v1.5. RESULTS: We included 64 D-CAA mutation carriers (mean age 49 years, 55% women, 55% presymptomatic). At least one white matter (WM) feature was seen in 55/64 mutation carriers (86%: 74% presymptomatic, 100% symptomatic). Fifteen (23%) mutation carriers, all presymptomatic, showed only WM features and no hemorrhagic markers. The sensitivity for probable CAA was similar between the new and the previous criteria: 11/35 (31%) in presymptomatic mutation carriers and 29/29 (100%) in symptomatic mutation carriers. The sensitivity for possible CAA in presymptomatic mutation carriers increased from 0/35 (0%) to 15/35 (43%) with the new criteria. CONCLUSION: The Boston criteria v2.0 increase the sensitivity for detecting possible CAA in presymptomatic D-CAA mutation carriers and, therefore, improve the detection of the early phase of CAA.

Corticosteroid-dependent plasticity mediates compulsive alcohol drinking in rats.

Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharin-sweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions [i.e., prefrontal cortex, nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST)], whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism.

Organic matter determination for street dust in Delhi.

The organic matter of street dust is considered as one of the causes for high human mortality rate. To understand the association, the street dust samples were collected from four different localities (industrial, residential, residential-commercial, and commercial) situated in the greater Delhi area of India. The loss-on-ignition method was used to determine the organic matter (OM) content in street dust. The OM content, potassium, calcium, sulfate, and nitrate concentrations of street dust in Delhi, India is measured to understand the spatial variation. Correlation analysis, analysis of variance, and factor analysis were performed to define the sources. The dust OM level ranges from 2.63 to 10.22 %. It is found through correlation and factor analysis that OM is primarily contributed from secondary aerosol and vehicular exhaust. The OM levels suggest that the use of a residential-commercial site for commercial purposes is polluting the street dust and creating the environmental and human health problems.

Minocycline for sporadic and hereditary cerebral amyloid angiopathy (BATMAN): study protocol for a placebo-controlled randomized double-blind trial.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a disease caused by the accumulation of the amyloid-beta protein and is a major cause of intracerebral hemorrhage (ICH) and vascular dementia in the elderly. The presence of the amyloid-beta protein in the vessel wall may induce a chronic state of cerebral inflammation by activating astrocytes, microglia, and pro-inflammatory substances. Minocycline, an antibiotic of the tetracycline family, is known to modulate inflammation, gelatinase activity, and angiogenesis. These processes are suggested to be key mechanisms in CAA pathology. Our aim is to show the target engagement of minocycline and investigate in a double-blind placebo-controlled randomized clinical trial whether treatment with minocycline for 3 months can decrease markers of neuroinflammation and of the gelatinase pathway in cerebrospinal fluid (CSF) in CAA patients. METHODS: The BATMAN study population consists of 60 persons: 30 persons with hereditary Dutch type CAA (D-CAA) and 30 persons with sporadic CAA. They will be randomized for either placebo or minocycline (15 sporadic CAA/15 D-CAA minocycline, 15 sporadic CAA/15 D-CAA placebo). At t = 0 and t = 3 months, we will collect CSF and blood samples, perform a 7-T MRI, and collect demographic characteristics. DISCUSSION: The results of this proof-of-principle study will be used to assess the potential of target engagement of minocycline for CAA. Therefore, our primary outcome measures are markers of neuroinflammation (IL-6, MCP-1, and IBA-1) and of the gelatinase pathway (MMP2/9 and VEGF) in CSF. Secondly, we will look at the progression of hemorrhagic markers on 7-T MRI before and after treatment and investigate serum biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov NCT05680389. Registered on January 11, 2023.

Regulation of human cortical interneuron development by the chromatin remodeling protein CHD2.

Mutations in the chromodomain helicase DNA binding protein 2 (CHD2) gene are associated with neurodevelopmental disorders. However, mechanisms by which CHD2 regulates human brain development remain largely uncharacterized. Here, we used a human embryonic stem cell model of cortical interneuron (hcIN) development to elucidate its roles in this process. We identified genome-wide CHD2 binding profiles during hcIN differentiation, defining direct CHD2 targets related to neurogenesis in hcIN progenitors and to neuronal function in hcINs. CHD2 bound sites were frequently coenriched with histone H3 lysine 27 acetylation (H3K27ac) and associated with high gene expression, indicating roles for CHD2 in promoting gene expression during hcIN development. Binding sites for different classes of transcription factors were enriched at CHD2 bound regions during differentiation, suggesting transcription factors that may cooperatively regulate stage-specific gene expression with CHD2. We also demonstrated that CHD2 haploinsufficiency altered CHD2 and H3K27ac coenrichment on chromatin and expression of associated genes, decreasing acetylation and expression of cell cycle genes while increasing acetylation and expression of neuronal genes, to cause precocious differentiation. Together, these data describe CHD2 direct targets and mechanisms by which CHD2 prevents precocious hcIN differentiation, which are likely to be disrupted by pathogenic CHD2 mutation to cause neurodevelopmental disorders.