Journal of Cerebral Blood Flow & Metabolism

BackgroundPeripheral microvascular abnormalities may reflect systemic microvascular dysfunction relevant to cerebral small vessel disease (cSVD), yet their relationship to individual neuroimaging markers and overall cSVD burden remains unclear. We evaluated whether abnormalities in nailfold capillaroscopy (NFC) are associated with specific cSVD markers and with the total cSVD score in a population-based cohort. MethodsAtahualpa residents aged [≥]60 years underwent NFC and brain MRI. Capillary tortuosities, dilatations, density, and megacapillaries were quantified using automated software with expert validation. Neuroimaging markers included white matter hyperintensities (WMH), lacunes, deep cerebral microbleeds (CMB), and enlarged basal ganglia perivascular spaces (BG-PVS). Logistic regression models assessed associations between NFC abnormalities and cSVD markers. Poisson regression was used to model the total cSVD score. All models were adjusted for demographics, educational attainment, and cardiovascular risk factors. ResultsAmong 289 participants (mean age 71.3 {+/-} 7.5 years; 51% women), lower capillary density was independently associated with CMB (OR: 0.70; 95% C.I.: 0.51-0.96) and lacunes (OR: 0.67; 95% C.I.: 0.50-0.91), with a borderline association for WMH (p=0.062). Megacapillaries were independently associated with moderate-to-severe WMH (OR: 5.01; 95% C.I.: 1.42-17.68). Tortuosities and dilatations showed no significant associations. Higher capillary density was inversely associated with the total cSVD score ({beta}: -0.179; 95% C.I.: -0.283 to -0.075). ConclusionsReduced capillary density and megacapillaries track with the burden of cSVD. NFC may provide a noninvasive window into cerebral microvascular health and could inform risk stratification for cSVD progression and related outcomes.

IntroductionCoronary artery disease (CAD) increases the risk of cerebrovascular events, yet early brain injury in this population remains poorly characterized. White matter hyperintensities (WMHs), a biomarker of cerebrovascular lesions, are prevalent in CAD and are linked to risk of stroke. Beyond total burden, spatial distribution of WMHs carries pathological significance and is critical for understanding CAD-related injury. While clinical outcomes including coronary revascularization procedure and myocardial infarction influence CAD prognosis, their impact on WMH burden remains unclear. MethodsThis study investigated regional WMH burden in CAD and its relationship with clinical characteristics. 82 adults over 50 years participated, including 44 individuals with CAD and 38 controls. WMHs were segmented from fluid attenuated inversion recovery and T1-weighted MRI and categorized as total, periventricular, deep, and superficial regions. History of myocardial infarction and coronary revascularization (coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI)), was obtained from medical files. ResultsIndividuals with CAD exhibited higher total, periventricular, and deep WMH volumes than controls. Participants who underwent CABG had higher superficial WMH volumes than those with PCI, suggesting greater disease severity influences WMH burden. ConclusionCAD is characterized by a distinct pattern of cerebrovascular vulnerability, with revascularization procedures influencing WMH burden

Objective: Cranial artery stenosis and dilatation are distinct large artery phenotypes that often coexist with cerebral small vessel disease (cSVD), yet their downstream microvascular functional correlates remain unclear. Methods: In the prospective Mild Stroke Study 3, we recruited patients with lacunar or mild non-lacunar stroke. At baseline, large artery stenosis (LAS), basilar artery dolichoectasia (BADE), and intracranial arterial diameters were assessed. Multimodal MRI quantified cerebrovascular reactivity (CVR), blood-brain barrier (BBB) permeability, plasma volume fraction, and intracranial pulsatility. cSVD markers were evaluated at baseline and 1 year. Associations between large artery phenotypes and vascular function were examined with multivariable regression. Mediation analyses tested whether vascular dysfunction linked large artery pathology to cSVD progression. Results: Among 224 participants (mean age 66.0, SD 11.2 years; 66.5% men), BADE (n=36, 16.1%) was independently associated with lower CVR in normal-appearing white matter (NAWM; {beta} -0.01, 95% CI -0.016 to -0.004, P=0.003). Larger mean intracranial arterial diameter was associated with lower CVR in NAWM and white matter hyperintensities (WMH), while showing a U-shaped association with BBB permeability. LAS (n=46, 20.5%) was unrelated to CVR, BBB permeability, or pulsatility, but was associated with higher plasma volume in WMH. CVR in NAWM partially mediated the association between BADE and both baseline cSVD burden and 1-year progression. Interpretation: Large artery dilatation may serve as a macroscopic signal of small-vessel dysfunction, being associated with lower CVR and altered BBB permeability. Reduced CVR in NAWM partially mediated the impact of dolichoectasia on cSVD progression and may represent a potential therapeutic target.

Post-stroke inflammation contributes to poor outcomes in both clinical and experimental studies. Interleukin-6 (IL-6) is a key inflammatory mediator in ischemic stroke, and higher circulating IL-6 levels are associated with greater stroke severity and worse clinical outcomes. Targeting IL-6 signaling therefore represents a potential therapeutic strategy. We tested whether inhibition of IL-6 signaling with the IL-6 receptor (IL-6R) blocking antibody tocilizumab (TCZ) improves recovery after experimental stroke. Aged mice (18-20 months) underwent 60 minutes of middle cerebral artery occlusion. TCZ (20 mg/kg) was administered 5 hours after ischemia onset, and behavioral outcomes were assessed weekly for 5 weeks. Delayed TCZ treatment improved long-term functional recovery in aged male mice but not in aged females. To explore this difference, we measured circulating soluble IL-6R (sIL-6R) levels in mice and patients with ischemic stroke. Females exhibited significantly higher post-stroke sIL-6R levels. Increasing the TCZ dose to 100 mg/kg restored efficacy in aged female mice and improved long-term outcomes. These findings support a role for IL-6R pathway modulation in improving recovery after experimental stroke and suggest that therapeutic response may differ by sex and target availability, potentially related to differences in circulating sIL-6R after ischemic injury.

PurposeLeft ventricular hypertrophy (LVH) is a major complication of chronic hypertension and an independent risk factor for cardiovascular morbidity and mortality. There are currently no clinically validated markers available to identify hypertensive individuals at risk for developing LVH. In hearts of hypertensive rats, we previously described metabolic changes that precede LVH development, including in branched-chain amino acid (BCAA) metabolism. This study investigated whether cardiac leucine uptake, measured with dynamic 5-[18F]fluoroleucine positron emission tomography-computed tomography ([18F]FLE-PET/CT), was impaired and could serve as an in vivo marker for hypertension-induced LVH development. ProceduresWe synthesized [18F]FLE following established radiochemistry protocols and performed dynamic [18F]FLE-PET/CT imaging in 3-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) control rats (n = 4 per group). Cardiac magnetic resonance (CMR) imaging was conducted on the same animals for structural co-registration. A dual-output reversible two-tissue compartment model with spill-over (SP) and partial volume (PV) corrections was developed to quantify the first-pass rate constant (K1) and total distribution volume (Vt = K1/k2) for [18F]FLE. Protein expression of L-type amino acid transporter 1 (LAT1) and branched-chain keto acid dehydrogenase (BCKDH) phosphorylation status were assessed by immunoblotting of isolated heart tissue. ResultsSHR demonstrated markedly lower first-pass leucine uptake rates (K1) and total distribution volumes (Vt) compared with WKY rats, consistent with reduced cardiac BCAA uptake. Concurrently, LAT1 (SLC7A5) expression was significantly reduced in SHR hearts compatible with decreased leucine uptake. Elevated BCKDH phosphorylation at Ser293 in SHR hearts indicated diminished BCKDH enzymatic activity and impaired BCAA catabolism. ConclusionsDynamic cardiac [18F]FLE-PET imaging successfully detects decreased leucine uptake in hypertensive rat hearts at 3 months of age, before LVH is established at 5 months. Reduced cardiac leucine uptake may thus serve as a surrogate marker for impaired cardiac BCAA metabolism and early in vivo indicator of cardiometabolic dysfunction that precedes LVH. The imaging approach holds translational potential for identifying hypertensive patients at risk for LVH progression.

Background: Vascular contributions to cognitive impairment and dementia (VCID) are thought to arise from distributed neurovascular unit (NVU) dysfunction rather than focal pathology, yet the transcriptional architecture of human VCID brain tissue and the status of endogenous counter-regulatory signaling within it remain incompletely characterized. Defining whether protective pathways are engaged and why they may be insufficient is critical for identifying therapeutic entry points in a disease lacking approved treatments. Methods: We performed differential gene expression analysis (DESeq2 v1.38.0) and pre-ranked gene set enrichment analysis (fgsea v1.24.0) on bulk RNA-sequencing data from superior parietal lobe tissue (GEO:GSE303449; n = 40; 19 VCID, 21 controls; model: age_scaled + Sex + condition), followed by Spearman correlation analysis, PI3K-Akt pathway level, leading-edge decomposition, and single-nucleus RNA-seq endothelial cell characterization (GEO:GSE282111). Results: No individual gene reached FDR < 0.05 for differential expression between VCID and control across 51,962 genes tested. Gene set enrichment analysis nonetheless identified eight significantly enriched pathway programs (all FDR < 0.05) that were upregulated, encompassing inflammatory, stress-response, cytoskeletal, and apoptotic signaling, consistent with distributed network-level dysregulation rather than dominant single-gene effects. The MAS1/ANG1-7 associated signaling gene set (54 genes) was the only counter-regulatory pathway achieving significance (NES = 1.381, FDR = 0.0127). MAS1 receptor expression was strongly (absolute Spearman's rho >= 0.64) and inversely associated with NF-kB pathway drivers TLR4 (Spearman's rho = -0.804) and IKBKB (Spearman's rho = -0.797; both FDR = 4.73 x 10^-9). Further, 9 of 12 correlations between MAS1 downstream effectors and endothelial activation markers were FDR-significant and positive, indicating that the downstream protective effector program is co-activated by inflammatory stress rather than directed by its receptor. Single-nucleus RNA-seq supports endothelial enrichment of the MAS1 pathway enrichment signal in VCID brain tissue. PI3K-Akt leading-edge decomposition revealed 96% gene-level non-overlap between inflammatory and vasoprotective arms. Conclusions: Human VCID brain tissue exhibits coordinated pathway-level dysregulation in the absence of dominant individual-gene effects, consistent with a disease driven by distributed transcriptional network stress. The MAS1/ANG1-7 vasoprotective axis is transcriptionally engaged and endothelially enriched, yet receptor expression is inversely associated with inflammatory signaling while downstream effectors remain transcriptionally engaged. This pattern suggests a failed compensatory state in the VCID superior parietal lobe. This architecture is consistent with a transcriptionally primed but receptor-constrained protective program. These findings suggest that therapeutic strategies restoring MAS1 receptor-level input to an already engaged downstream program may represent a plausible therapeutic strategy for VCID, pending experimental validation.

Perinatal hypoxia is a major contributor to neurodevelopmental disorders; however, the consequences of mild-to-moderate perinatal hypoxia (MPH) remain insufficiently characterized. Here, we investigated cortical plasticity following MPH using a multimodal approach that combines behavioral assessment, histological analysis, and in vivo magnetic resonance imaging (MRI). Fifty-six Wistar Han rats were exposed to hypoxia or normoxia at postnatal day 1 (P1). Neurodevelopmental assessment from P3 to P14 revealed impaired rooting and vibrissae-placing reflexes in hypoxic rats. Histological analysis demonstrated: altered expression of microtubule-associated protein-2, apical dendrite bundling, reduced neurofilament-H expression, and decreased dendritic arbor complexity in large pyramidal neurons, indicating disrupted maturation of excitatory circuits. Increased parvalbumin expression, higher interneuron density, and its enhanced neurite elaboration indicated precocious development of inhibitory circuits, consistent with a compensatory response. MRI at P15, combined with whole-brain voxel-wise analysis, revealed a significant increase in fractional anisotropy in the anterior cingulate cortex (ACC). Convergent behavioral, histological, and imaging findings identified the ACC as the most vulnerable region following MPH, followed by the somatosensory cortex. These findings reveal early cytoarchitectural and MRI detectable correlates of a single episode of MPH, which, together with previous findings from this model, support the neurodevelopmental origin of persistent alterations in cortical structure and circuit function, characterized by an excitatory-inhibitory imbalance. The study identifies and defines a framework for understanding region-specific vulnerability and plasticity in the immature brain, with implications for improving the early detection of subtle perinatal brain injury, as a prerequisite for timely therapeutic intervention.

Colony stimulating factor 1 receptor (CSF1R) is a tyrosine kinase receptor that is expressed exclusively in microglia within the CNS. Its endogenous ligands, colony stimulating factor-1 (CSF1) and interleukin-34 (IL-34), are released from neurons, positioning CSF1R as a key mediator receptor of neuron-glia communication. CSF1R is considered not only a potential drug target, but also a biomarker of neuroinflammation. From that perspective, selective radioligands for neuroimaging are of great interest for imaging neuroinflammation and determining drug occupancy. In this study, we have validated the binding characteristics of a CSF1R inhibitor, 4-((5-MethOxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine (5-MOP) as a novel CSF1R radioligand, by performing in vitro saturation binding experiments in human and murine tissues. 5-MOP was found to be selective for CSF1R among a broad range of kinases. Autoradiography revealed that [3H]5-MOP binds with high affinity (KD = 9.8 nM) to a single saturable binding site in human meningioma tissues, and this binding was displaced with known CSF1R inhibitors, including CPPC, sCSF1inh and GW-2580. In contrast, CPPC, which has been extensively used as a CSF1R radioligand showed substantial cross-reactivity to other brain kinases, including Trk A/B/C, and [3H]CPPC could only be displaced with CPPC itself, not by other ligands, including 5-MOP. These results identify [3H]5-MOP as the most selective radioligand currently available, enabling accurate detection of drug occupancy and activated microglia. Significance of the studyThis study identifies and validates a novel selective radioligand that binds CSF1R with high selectivity and low nanomolar affinity. Because CSF1R is selectively expressed in activated microglia, this radioligand could be useful for detecting neuroinflammatory activity.

BackgroundImpairment of brain waste removal contributes to Alzheimers disease etiology and progression. Although hypertension is a risk factor for dementia, little is known about how it affects measures of clearance in human brain. MethodsCross-sectional (n=159) and longitudinal (n=94) analysis of the relationship between blood pressure (BP) and brain clearance. The estimate of brain clearance was measured using positron emission tomography (PET) as the rate of radiotracer (MK-6240) efflux from the lateral ventricles in the 10-30-minute window after tracer injection. We also examined cerebral blood flow, PET-derived tau deposition in the medial temporal lobe, cognition and plasma biomarkers of neurodegeneration. At baseline we compared participants with (n=88) and without (n=71) hypertension. For longitudinal analyses we defined two groups based on systolic BP trajectories from baseline to follow-up: as long-term controlled (n=76) or uncontrolled BP (n=18). ResultsAt baseline, subjects with hypertension had lower ventricular clearance than normotensive controls (Cohens d=0.53, p=0.001). Over the course of the observation period (median 1.85 years) subjects in the uncontrolled BP group experienced a steeper reduction in clearance rates ({beta}=-5.88) than subjects in the controlled BP group ({beta}=-0.81, interaction p=0.039). ConclusionsOur study suggests that hypertension impairs brain clearance of fluids.

Background and PurposeDespite high rates of macrovascular recanalization, approximately half of patients with large vessel occlusion stroke fail to achieve functional independence after endovascular thrombectomy (EVT). Residual tissue-level perfusion abnormalities on post-procedural CT perfusion (CTP) may indicate futile recanalization and inform selection for adjuvant therapy. We synthesized post-EVT CTP thresholds, summarized acquisition timing, and discussed implications for patient selection in trials of intra-arterial thrombolysis, antithrombotics, and neuroprotection, limited to studies performing perfusion imaging after EVT. MethodsWe searched MEDLINE, EMBASE, and the Cochrane Library (January 2018-April 2026) for studies performing perfusion imaging after EVT, reporting [&ge;]1 quantitative CTP parameter with functional or neurological outcome, and enrolling [&ge;]10 patients; pre-EVT CTP studies were excluded. Functional independence with versus without post-EVT hypoperfusion was pooled using DerSimonian-Laird random-effects. Individual patient data from our prospective Cerebrolysin proof-of-concept cohort (N=18) were integrated. ResultsNine post-EVT perfusion imaging studies (497 patients) met inclusion criteria. Residual hypoperfusion occurred in 21-53% of angiographically successful reperfusions and was associated with lower odds of functional independence (pooled OR 0.23, 95% CI 0.17-0.33; I{superscript 2}=29%). A Tmax >6 s volume <3.5 mL at 30-90 minutes post-EVT was the most consistently validated threshold (OR 3.5, 95% CI 1.6-7.8). In our cohort, an ischemic core (rCBF <30%) of 0 mL versus any detectable residual core was associated with markedly higher odds of independence (OR 27.5, 95% CI 1.0-746 with continuity correction; {rho}=0.77, p=0.003). The optimal CTP acquisition window is 30-120 minutes post-EVT. ConclusionsPost-EVT CTP outperforms modified TICI grading for predicting functional outcome and identifies biologically distinct subgroups for adjuvant therapy selection. Standardized post-EVT CTP at 30-120 minutes, applied with the proposed threshold framework, should be used for eligibility and stratification in future trials of intra-arterial thrombolysis, antithrombotics, and neuroprotection.

The metabolic demands of the human brain are met by a complex vascular architecture, yet our characterization of this network remains incomplete. While we have mapped the macroscopic vessels on the brains surface and the microscopic capillaries within small tissue samples, the mesoscopic scale consisting of the penetrating vessels that plunge through cortex remains an anatomical terra incognita. Mapping the interface between the macroscopic and microscopic scales is essential to understanding the critical vascular supply that sustains brain health. Here, we leveraged the BigBrain dataset and developed custom detection and tracing algorithms to reveal a whole-cortex record of the mesoscopic vascular network. We find that vascular density is not uniform across the cortex, but is a heterogeneous landscape that shows clear relationships to traditional areal boundaries. While based on a single human specimen, our results constitute a reference for human mesoscopic angioarchitecture and demonstrates the power of repurposing high-resolution histological atlases. Ultimately, this work lays the groundwork for validating recently developed in vivo MRI techniques for imaging the human cerebrovascular system at mesoscale.

Basal forebrain cholinergic neurons project widely to the cerebral cortex and participate in cerebrovascular regulation. Although cholinergic axons are distributed around the cerebrovasculature, their functional relationship with arteriolar dynamics remains unclear. In this study, we established an in vivo two-photon imaging approach to simultaneously measure Ca2+ signals in cholinergic axonal varicosities and arteriolar diameters in urethane-anesthetized mice. An adeno-associated virus (AAV) vector (rAAV-ChAT-jGCaMP8s) was injected into the nucleus basalis of Meynert. In vivo imaging of the frontal cortex revealed bead-shaped GCaMP signals around the arterioles. Pinch stimulation transiently increased Ca2+ signals in periarteriolar varicosities, followed by arteriolar dilation, with an approximately 2-s delay between their peaks. Linear regression analysis disclosed a significant relationship between the magnitudes of these changes. This approach enabled simultaneous evaluation of cholinergic axonal activity and arteriolar dynamics in vivo, providing a tool to investigate the cholinergic regulation of cerebrovasculature. HighlightsO_LIAAV-ChAT-GCaMP enables selective imaging of cholinergic projections C_LIO_LITwo-photon imaging reveals bead-shaped Ca2+ signals around arterioles C_LIO_LISensory stimulation increases periarteriolar cholinergic axonal Ca2+ signals C_LIO_LIAxonal Ca2+ signals are associated with arteriole dilation C_LI

Cerebral small vessel disease (cSVD) is a major contributor to stroke and cognitive decline, ultimately leading to vascular dementia (VaD). Genetic factors play a key role in the disease susceptibility and progression, and variants in COL4A1 cause one of the most common genetic cSVD. COL4A1 encodes the 1 subunit of type IV collagen, the principle extracellular matrix (ECM) protein in the basement membrane of vasculature. In the central nervous system (CNS), the neurovascular unit (NVU) has the unique astrocyte-derived parenchymal basement membrane (pBM), in addition to the vascular basement membrane (vBM), which together contributing to the regulation of the blood-brain barrier (BBB) function. However, the role of pBM in cSVD remains under investigated and poorly understood. The lack of relevant human models has limited our ability to dissect specific cell-cell and cell-matrix interactions, hindering the identification of effective therapeutic targets. In this study, we hypothesised that astrocyte-mediated ECM remodelling contributes to BBB dysfunction in COL4A1-associated cSVD. To investigate this, human induced pluripotent stem cells (hiPSCs) derived from a patient carrying the COL4A1G755R variant and its isogenic control line were differentiated into astrocytes and brain microvascular endothelial cells (BMECs). Comparing to isogenic controls, the COL4A1G755R astrocytes significantly reduced the expression of ECM-related genes and abnormally increased glutamate uptake. ECM preparations from COL4A1G755R astrocytes significantly damaged the tight junction (TJ) structure formed by control iPSC-derived BMECs and failed to rescue the compromised TJ integrity in COL4A1G755R BMECs. The secretome from COL4A1G755R astrocytes exaggerated the ECM abnormality in COL4A1G755R BMECs. Most importantly, reduced expression of HTRA1, a crucial serine protease known to regulate both ECM turnover and homeostasis, and increased TGF-{beta} signalling was observed in COL4A1G755R astrocytes. Functional rescue by recombinant human HTRA1 protein restored the disrupted TJ continuity in COL4A1G755R BMECs and normalized TGF-{beta} signalling and glutamate uptake in astrocytes. Together, these findings defined a previously unrecognised astrocyte-driven pBM mechanism in COL4A1-associated cSVD and highlight HTRA1 in ECM remodelling as a therapeutic target.

Task-evoked decreases in blood-oxygenation-level-dependent (BOLD) signals are a well-recognized phenomenon in functional magnetic resonance imaging (fMRI) studies. These deactivations are most prominent in the default mode network (DMN), a set of regions most active at rest. The metabolic basis of task-induced BOLD fMRI deactivations remains unclear. To address this question, we used PET/MRI to simultaneously measure BOLD fMRI and cerebral glucose consumption (CMRglc) during visuomotor and language tasks in 22 cognitively unimpaired older adults (15 female, 7 male). Task performance increased BOLD signals in task-relevant regions and decreased BOLD signals in the DMN. Positive BOLD responses generally coincided with increases in CMRglc. In contrast, CMRglc did not decrease in regions showing negative BOLD responses; instead, it typically increased. In particular, the posterior cingulate cortex showed significant CMRglc elevations in conjunction with negative BOLD responses. Whole-brain intensity normalization partially restored task-induced decreases in CMRglc, indicating that relative reductions appear in regions in which CMRglc increases are smaller than the global average. Overall, our results imply that BOLD fMRI deactivations can occur in conjunction with stable or even increased glucose consumption.

Hypoxia-targeted BOLD MRI is a novel technique, which probes oxygenation physiology in response to a controlled transient hypoxia stimulus. In glioblastoma, the signal response is spatially and temporally heterogeneous. We developed a voxel-wise temporal decomposition framework for hypoxia-targeted BOLD MRI that separates the arrival of responses, transition phases, and steady state during controlled isocapnic hypoxia. Twenty healthy controls underwent 3-T BOLD MRI during a double hypoxic step challenge to establish a normative reference. Three patients with newly diagnosed glioblastoma were included as proof-of-concept cases. For each voxel, we estimated response arrival delay (Delaycorr), delay to plateau, delay to return and an O2-normalized steady-state response (HypoxiaSS). Healthy-control maps were used to construct a voxel-wise normative atlas and, for HypoxiaSS, a global-response-adjusted model for patient deviation mapping. In healthy controls, HypoxiaSS showed lower supratentorial between-subject variabilitythan both whole-stimulus comparators (coefficient of variation: 1.77 versus 2.36 for Hypoxiaavg) and higher voxel-level step-to-step agreement (ICC(2,1): median 0.951 versus 0.792 for Hypoxiaavg). Whole-stimulus averaging exhibited a systematic step-2 signal amplification present in 19 of 20 subjects, which was absent from HypoxiaSS. Asingle global response scalar explained a median 72.5% of voxel-wise between-subject variance in HypoxiaSS. In proof-of-concept patient analyses, G-adjusted HypoxiaSS deviation maps and timing maps identified spatially coherentabnormalities that were partly complementary and extended beyond conventional MRI-defined lesion margins.Temporal decomposition improves the stability and interpretability of hypoxia-targeted BOLD MRI and provides a practical framework for population-referenced physiological mapping and atlas-based deviation mapping in glioblastoma.

Background: Amyloid-beta PET provides critical biomarker data for Alzheimer's disease diagnosis and anti-amyloid therapy evaluation, yet low spatial resolution and partial volume effects result in decreased interpretability, particularly in cases with low or borderline cortical amyloid burden. While quantitative metrics (SUVr, Centiloid) aid in interpretation of amyloid burden, disagreement between visual reads and quantitative burden does occur, further blurring the line between positive or negative scans. We evaluated whether a vendor-neutral MR-guided PET denoising and resolution enhancement method (MRG) that uses Bowsher regularization improves image interpretability and reader performance while preserving established quantitative biomarkers across multiple amyloid tracers, leading to increased concordance among visual reads and quantitative metrics. Methods: Standard (STN) and MRG PET images were compared for four tracers ([18F]AV-45 ([18F]florbetapir, FBP), [18F]florbetaben (FBB), [18F]flutemetamol (FMM), and [11C]Pittsburgh compound-B (PiB) collectively from 24 MRI and 33 PET scanners. Quantitative equivalence was assessed by comparing Standardized Uptake Value ratio (SUVr) and Centiloid scores. In three of the four tracers (FBP, FBB, FMM), visual-quantitative concordance (AUC) and reader performance were evaluated in a blinded multi-reader study by four highly experienced brain PET readers who assessed image quality, artifact severity, reader confidence, and binary amyloid positivity. Results: Across all tracers, MRG preserved quantitative SUVr and Centiloid metrics relative to STN (R2 >0.90 for all tracers) without introducing bias to the SUVr metric. Concordance between visual reads and quantitative burden measures significantly improved with MRG. In the multi-reader study, MRG resulted in significantly higher image quality, lower artifact burden, and greater reader confidence compared to STN (p < 0.0001). Reader accuracy increased from 0.89 to 0.94, and the false-negative rate decreased from 0.08 to 0.04. Crucially, improvements in reader confidence, accuracy, and the reduction in false negative reads were most pronounced in cases with low amyloid burden near the threshold of visual positivity. Conclusions: MRG denoising and resolution enhancement improved perceived image quality, reader confidence, and accuracy for amyloid PET while preserving standard quantitative behavior across tracers. By improving cortical definition in visually challenging low-burden cases without disrupting established SUVr/Centiloid behavior, MRG may reduce visual-quantitative discordance and support more confident amyloid PET interpretation near the threshold of positivity.

BackgroundHemorrhagic transformation (HT) is a frequent and serious complication, occurring in up to 40% of cases after endovascular treatment (EVT) for acute ischemic stroke (AIS). Inflammation has been increasingly recognized as a key factor influencing both stroke pathophysiology and post-treatment complications (such as HT) interacting with endothelial dysfunction to exacerbate vascular injury after EVT. The objective of this study is to evaluate whether systemic inflammatory status predicts HT in AIS patients, and its relationship with endothelial biomarkers in the setting of this complication. MethodsWe retrospectively reviewed a prospective cohort of 229 AIS patients treated with EVT. Demographic, clinical, imaging, and laboratory data were collected. Inflammatory markers included white blood cell subsets and indices such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-neutrophil ratio (PNR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI). Endothelial function was assessed by flow-mediated dilation (FMD) and circulating homoarginine (HArg), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). The main outcome was radiological or symptomatic HT, classified according to ECASS criteria. ResultsHT was observed in 92 patients (40.2%), of whom 35 (36.1% of HT and 15.3% of the total) were symptomatic. In multivariate analysis, independent predictors of HT included higher NIHSS at admission, higher plasma glucose at admission, the use of non-aspiration devices, lower pre-recanalization lymphocyte count, higher pre-recanalization SII and higher NLR levels. Among endothelial function markers, HArg correlated with inflammatory markers, ANC (r = -0.2) and WBC (r = -0.19), and was associated to PH and symptomatic HT, but not with any radiologic HT after AIS. ConclusionsAn altered inflammatory status prior to EVT in AIS patients is associated with an increased risk of developing HT after EVT. Additionally, endothelial dysfunction could participate in the more aggressive forms of this complication.

IntroductionHealthy and diseased placentae alike often display some degree of pathology. However, quantitative techniques to characterize common pathologies and their relationship to local maternal hemodynamics in healthy primate placentae are currently limited. MethodsPlacentae from seven rhesus macaques were imaged by MRI at three time points across mid-to late-gestation, to quantify placental blood volume, flow, and perfusion from maternal spiral arteries across pregnancy. Near term, we collected placental cotyledons, digitized hematoxylin/eosin-stained slides, then segmented and annotated sub-tissues and major pathologies (intervillous gaps, fibrin deposition, villous agglutination, inflammatory agglutination, and stromal mineralization) within each cotyledon. Individual pathologies were assessed in relation to each other and MRI perfusion metrics, in a cotyledon-specific manner. Parallel analyses were performed to investigate both basic (Spearman correlation) and animal variance-negated (dimensionality-reduction) relationships. ResultsCotyledons with increased stromal mineralization demonstrated low blood perfusion across pregnancy, alongside significant compensatory changes. Mineralization was further associated with decreased fetal weight, across all sub-tissues. Dimensionality reduction revealed maternal vascular malperfusion-associated pathologies as the largest contributor to dataset variance. Additionally, pathologies commonly associated with healthy placental function demonstrated low cotyledon blood flow and volume at all timepoints, with no evidence of compensatory changes across gestation. ConclusionsComprehensive digital annotation revealed several relationships connecting pathology and maternal blood perfusion in the healthy primate pregnancy, at the smallest functional unit of the placenta. This methodological framework embeds pathologist-refined morphological expertise into a quantitative, spatially resolved format that can ground, rather than be replaced by, unsupervised computational approaches to placental analysis.

BackgroundMagnetic resonance imaging (MRI) is critical for acute stroke triage, but time-consuming, and often requires contrast injection for perfusion imaging. This study aimed to synthesize T-map perfusion maps from routinely available, non-contrast DWI and FLAIR using deep generative models. We hypothesized that relevant perfusion information could be inferred from these modalities to streamline imaging and reduce reliance on dynamic susceptibility contrast perfusion. MethodsAcute MRI data from 355 patients with anterior circulation stroke, including dynamic susceptibility contrast perfusion, were retrospectively collected from two European centers (Heidelberg: 2010-2018; Bordeaux: 2021-2022). Six versions of a denoising diffusion probabilistic model (DDPM) and a GAN architecture were trained to generate synthetic T-max perfusion maps from DWI, FLAIR, and infarct core mask as inputs. Performance was assessed by comparing synthetic and ground truth T-max maps using image similarity metrics. Regions with T-max >6s were compared using Dice coefficients, and mismatch volume distributions were analyzed. An ablation study quantified the contribution of each input. ResultsThe best performance was achieved by a DDPM with a 2.5D architecture using DWI, FLAIR, infarct core mask, and a perfusion-weighted loss function. It produced synthetic perfusion T-max maps with high similarity to ground truth under 110 seconds. The model showed strong spatial overlap for T-max >6s regions in internal validation (average Dice = 0.82, SD = 0.08), and external validation average (Dice 0.59, SD = 0.13), respectively. Synthetic maps closely matched ground-truth mismatch distributions, capturing key perfusion patterns. The infarct core mask played a critical role in model performance, alongside DWI and FLAIR inputs. ConclusionsWe propose a non-invasive, scalable framework to generate synthetic T-max perfusion maps from non-contrast MRI. This approach could expand access to perfusion data in acute stroke, shorten imaging protocols, and accelerate treatment decisions by eliminating the need for contrast-enhanced acquisition. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/684079v2_ufig1.gif" ALT="Figure 1"> View larger version (94K): org.highwire.dtl.DTLVardef@164235forg.highwire.dtl.DTLVardef@14e5489org.highwire.dtl.DTLVardef@190214eorg.highwire.dtl.DTLVardef@17a9e3a_HPS_FORMAT_FIGEXP M_FIG C_FIG

PurposeTo present the design and validation of a lowcost, microcontrollerbased gas delivery system that automates fixed inspired respiratory stimuli for MRI experiments. MethodsThe system uses three solenoid valves controlled by an Arduinobased circuit to switch between premixed medical gas cylinders according to predefined timing protocols. By using the MRI scanner external timing signal, gas delivery can be synchronised with image acquisition. Both a permanently installed configuration and a portable enclosure were constructed using commercially available components, with a total material cost of approximately {pound}650. The system was integrated with a singleuse breathing circuit and evaluated using hypercapnic and hyperoxic stimulus paradigms. Endtidal oxygen and carbon dioxide were measured using a respiratory gas analyser and physiological responses were assessed using BOLD MRI at 3 T. ResultsThe system delivered reliable, repeatable gas transitions during MRItriggered protocols. During hypercapnia (n{square}={square}15), the mean increase in endtidal carbon dioxide was 8.7{square}{+/-}{square}1.8{square}mmHg from a baseline of 32.2{square}{+/-}{square}3.1{square}mmHg, producing a mean grey matter BOLD signal increase of 3.2{+/-}1.7%. During hyperoxia (n{square}={square}15), the mean increase in endtidal oxygen was 292.3{square}{+/-}{square}59.0{square}mmHg from a baseline of 114.5{square}{+/-}{square}10.7{square}mmHg, with an associated BOLD signal change of 1.2{+/-}1.7%. Across both protocols respiratory and BOLD responses were consistent across participants. ConclusionThis microcontrollerbased system provides an inexpensive and reliable method for administering fixed inspired respiratory stimuli with automated MRI synchronisation. It offers an intermediate option between simple manual systems and higher cost commercial gas blenders, making it well suited for technical and methodological studies in cerebrovascular reactivity, hyperoxiaBOLD and related applications.