Journal of Cerebral Blood Flow & Metabolism

Traumatic brain injury (TBI) is the main cause of death and disability in the United States in people younger than 35 years old and is a common cause of wartime injuries. Mild TBI (mTBI) is a predisposing factor for later development of dementia and cerebrovascular disease. Aerobic exercise was reported to improve cognitive function in chronic TBI through improved vascular function. The aims of the study are to characterize and correlate the subacute (10 weeks) and chronic (12 months) cognitive and cerebrovascular functional impairment following mTBI and evaluate the modulating effect of exercise early or late following mTBI on these changes. Sprague-Dawley rats received midline fluid percussion injury or sham procedure and followed for 10 weeks or 12 months with a subgroup of mTBI rats undergoing 5-week treadmill aerobic exercise 2 weeks (early) or 10 months (late) post-injury for 6 weeks. Cognitive function was assessed using novel object recognition (NOR) and novel object location (NOL) tests. Regional cerebral blood volume (CBV) and cerebrovascular reactivity following hypercapneic stimulation (CVR) using contrast magnetic resonance imaging (MRI) and ex vivo pial artery vasoreactivity to intraluminal pressure, angiotensin II and diethylenetriamine NONOate (DETA NONOate) were measured. There was no difference in NOR or NOL at 10 weeks between mTBI and sham. NOR, but not NOL, was reduced in mTBI rats at 12 months. CBV at 10 weeks was higher in the primary somatosensory trunk cortex (trunk) and dentate gyrus regions in mTBI, but not at 12 months. CVR was lower in the trunk region of mTBI rats at 12 months. Compared to sham response at 10 weeks, there was impaired arterial constriction response to 90 mm Hg intraluminal pressure in mTBI rats at 10 weeks and in sham and mTBI rats at 12 months, with no difference seen in response to angiotensin II or DETA-NONOate exposure. There was no correlation between cognitive and vascular outcomes at 10 weeks or 12 months. Early or late exercise did not affect 12-month cognitive or vascular function following mTBI. The study showed chronic impairment in short-term memory cognitive function, regional cerebrovascular reactivity and early onset of impaired cerebrovascular myogenic response in rats subjected to mTBI. The findings of persistent cognitive and cerebrovascular impairment in this animal model enhance our understanding of the long-term consequence of mTBI.

Background. Cerebrovascular reactivity (CVR) is a sensitive marker of vascular health, most commonly measured with BOLD fMRI during hypercapnic gas challenges. Hypoxia is a complementary but under-characterized vasoactive stimulus. We characterize a combined hypercapnic-hypoxic gas-challenge paradigm at 7 Tesla BOLD fMRI and its cross-session reproducibility. Methods. Eleven healthy adults were scanned twice at 7 Tesla during an 18-minute multi-echo, multiband BOLD acquisition, receiving fixed-inspired hypercapnic (5% CO2) and hypoxic (10% O2) gas boluses separated by medical-air recovery periods, with end-tidal gas and peripheral saturation monitoring. Hypercapnic and hypoxic CVR were estimated using three trace-based general linear models: end-tidal gas, peripheral saturation, and Severinghaus-derived arterial saturation; and a finite impulse response model. Cross-session reproducibility was assessed by region-of-interest intraclass correlation. Results. The paradigm produced robust, condition-specific gray-matter BOLD responses that reproduced across sessions. The Severinghaus-derived saturation regressor generalized significantly better than end-tidal and peripheral regressors under cross-session validation and outperformed the finite impulse response benchmark in 58% of gray-matter voxels. Reproducibility across cortical, subcortical, and brainstem atlases was moderate-to-high (median cortical intraclass correlation 0.71). Conclusion. A combined hypercapnic-hypoxic paradigm yields reproducible voxelwise cerebrovascular reactivity maps at 7 Tesla; Severinghaus-derived arterial saturation is the most generalizable regressor for hypoxic reactivity.

Background Mitochondrial dysfunction and abnormal cerebral energy metabolism are implicated in many neuropsychiatric and neurodegenerative disorders. 13C magnetic resonance spectroscopy (MRS), combined with 13C-labeled substrate infusion, offers a non-ionizing, minimally invasive method for assessing fluxes through the main cerebral energy metabolism pathways. However, its human application at 7 T has not been fully established, especially within the frontal lobe. Purpose To explore a clinically translatable interleaved 1H/13C MRS protocol for quantification of cerebral glucose uptake and downstream metabolism at 7 T, and to estimate the tricarboxylic acid (TCA) cycle flux (VTCA) for validation. Study Type Prospective. Population Three young healthy volunteers. Field Strength/Sequence 7T; ACE-STEAM (indirect 1H-[13C]) and ISIS-DEPT (direct 13C-[1H]). Assessment ACE-STEAM and ISIS-DEPT were applied to acquire the time-resolved spectra in the frontal lobe. 13C-labeled glucose, glutamate, and glutamine fractional enrichment time courses were quantified to estimate VTCA through the one-compartment model. Statistical Tests The relative estimated fitting uncertainties (EFUs) were reported for the processed spectra. Nonlinear least squares minimization was used for flux fitting of 13C traces. Uncertainty of the estimated metabolic fluxes was evaluated using Monte-Carlo simulations. Results [1-13C]-glucose (GlcC1) was detected immediately on 13C MR spectra, followed by 13C-labeled GluH4 and GlnH4 and then GlxH3 can be quantified on 1H MR spectra. End-of-infusion mean enrichments were 17% (GluH4), 13% (GlnH4), and 7% (GlxH3). Brain glucose concentration ranged 1.86-2.94 mM, with 61% of the mean enrichment in C1. Group-average VTCA was 0.66 {+/-} 0.07 mol/g/min. Data Conclusion This interleaved 1H/13C MRS protocol enables minimally invasive quantification of cerebral metabolic fluxes, may provide a useful framework for investigating neuropsychiatric and neurodegenerative diseases at 7 T. Evidence Level 1. Technical Efficacy Stage 1.

Background: Alterations in excitatory and inhibitory neurotransmission contribute to stroke pathology and recovery, yet longitudinal assessment of these changes in vivo remains limited. We investigated the feasibility of longitudinal edited proton magnetic resonance spectroscopy (1H-MRS) to quantify {gamma}-aminobutyric acid (GABA) and glutamate following experimental focal cerebral ischaemia. Methods: Male rats underwent endothelin-1-induced striatal ischaemia or sham surgery. Longitudinal edited 1H-MRS was performed at baseline and 2-, 7- and 30-days post-stroke at 7-tesla with a MEGA-sLASER sequence. A voxel was positioned within the ipsilesional motor cortex adjacent to the lesion. Behavioural outcomes (grip strength, adhesive removal and CatWalk gait analysis) were assessed alongside spectroscopy, and immunohistochemistry for Iba1, GFAP and ICAM-1 was performed at 30 days. Results: Stroke induced a transient reduction in GABA+/tCr within the ipsilesional motor cortex, with significantly lower concentrations than sham animals at 7 days (p<0.05), returning to baseline by 30 days. Glutamate/tCr and GABA/glutamate ratio were unchanged throughout the study. Behavioural deficits were mild, with significant effects on motor outcomes such as grip strength, gait swing speed and paw placement, while sensory areas of the brain seemed largely unaffected. Histological analysis revealed no persistent differences in cortical Iba1, GFAP or ICAM-1 immunoreactivity at 30 days. Conclusions: Longitudinal 1H-MRS is a feasible approach for monitoring dynamic changes in inhibitory neurochemistry following experimental stroke. The transient reduction in peri-lesional GABA, despite minimal behavioural impairment and an absence of persistent cortical inflammation, supports the use of edited spectroscopy as a translational tool to investigate neurochemical mechanisms underlying network dynamics in post-stroke recovery.

INTRODUCTION: We examined whether stroke induces chronic cerebrovascular dysfunction and thereby exacerbates A{beta} pathology. METHODS: We exposed Tg2576 mice to a transient mild subcortical ischemia and examined cerebrovascular function at chronic timepoints as well as reactive astrocytes and A{beta} deposition post-mortem. RESULTS: Baseline cerebral blood flow and cerebrovascular reactivity (CVR) are both influenced by anesthesia regimen. A{beta} strongly impairs CVR at earlier ages, while mild ischemia impairs CVR at later ages. Mild ischemia reduces neurovascular coupling more strongly than A{beta} and synergistically increases A{beta} deposition in Tg2576 mice. DISCUSSION: Stroke-induced cerebrovascular dysfunction and astrocyte reactivity persist for long periods after the injury. Although there is variability in the spatiotemporal progression of ischemia- and A{beta}-induced vascular impairments, they generally follow the pattern of Thal staging. Surprisingly, the ischemia+A{beta} group showed the least cerebrovascular dysfunction yet an exacerbation of A{beta} deposition, suggesting that these pathologies are connected but not tightly coupled.

Background: Positron emission tomography (PET) myocardial perfusion imaging (MPI) provides complementary information on perfusion, myocardial blood flow and ventricular function. While these markers are often considered collectively during interpretation, their quantitative integration with imaging and clinical data into a unified predictive framework remains limited. We developed a multimodal artificial intelligence framework that combines PET polar maps with quantitative imaging and clinical features to improve obstructive coronary artery disease (CAD) detection. Methods: We retrospectively analyzed the multicenter REFINE PET registry. Among 38,682 PET MPI studies from 14 sites, 2,833 patients without known prior CAD underwent invasive coronary angiography within 180 days. Obstructive CAD was defined as >=50% left main stenosis or >=70% stenosis in other major epicardial coronary arteries. We developed a two-stage contrastive learning framework to learn multimodal PET representations from studies without angiographic labels and transfer them to supervised CAD prediction. In Stage 1, PET image and tabular encoders were pretrained on 12,225 PET MPI studies from eight development sites using 15-channel PET polar maps, quantitative PET perfusion, flow and gated functional measures, and clinical variables. In Stage 2, the pretrained encoders and a lightweight classification head were fine-tuned in 968 angiography-labeled patients, using lower encoder learning rates to limit overfitting. The model was externally validated for angiographically defined obstructive CAD detection in 1,865 patients from six independent sites and compared with standard PET MPI metrics. Results: The prevalence of obstructive CAD was 60% in the training cohort (66% male, median age of 70 years [63, 77]), and 55% in the external validation cohort (64% male, median age of 67 years [60-74]). In external validation, the AI model achieved an AUC of 0.85 (95% confidence interval (CI), 0.83-0.87) for obstructive CAD detection and outperformed conventional quantitative PET metrics (all P < 0.001). At a specificity matched to visual summed stress score, the AI model achieved higher sensitivity (89% [95% CI, 87-91] versus 85% [95% CI, 82-87]) and negative predictive value (81% [95% CI, 77-84] versus 73% [95% CI, 69-77]; both p<0.001). The overall net reclassification improvement was 8.9% (95% CI, 4.2-13.6%; p = 0.001). Conclusions: Multimodal contrastive pretraining improved obstructive CAD detection from PET imaging beyond conventional perfusion-based scoring in independent multisite external validation.

Reperfusion is the cornerstone of acute ischemic stroke treatment, yet how it reshapes the temporal trajectory of neurovascular injury beyond the acute phase remains unclear. Here, we developed permanent (pStroke) and transient (tStroke) cortical ischemia mouse models compatible with longitudinal in vivo two-photon imaging to investigate the evolution of neurovascular injury following ischemia and reperfusion. Although reperfusion markedly reduced acute infarct development and neuronal loss, it failed to restore neurovascular homeostasis. Longitudinal two-photon imaging of ischemic mice revealed neuronal hyperexcitability and aberrant network synchronization, concomitant with impaired vascular remodeling and sustained vascular leakage following reperfusion. Histological analyses further demonstrated progressive neurodegeneration, chronic microglial activation and persistent alterations in the neurovascular unit despite improved preservation of brain tissue during the acute phase. Analysis of dextran permeability revealed size-selective BBB dysfunction, indicating that reperfusion induces prolonged impairment of vascular barrier properties rather than complete vascular recovery. Together, our findings demonstrate that reperfusion might reshape the temporal evolution of ischemic brain injury by limiting acute tissue damage while also promoting chronic neurovascular dysfunction, identifying persistent vascular instability as a potential therapeutic target for improving long-term recovery after ischemic stroke.

Preclinical stroke research is severely hampered by the lack of high-throughput, quantitative perfusion imaging tools capable of bridging the gap between functional hemodynamics and structural injury. The emerging second near-infrared (NIR-II) fluorescence imaging offers superior spatial resolution and tissue penetration, but its utility remains restricted by a lack of standardized analysis protocols and inability to resolve in-depth infarct regions. Here, we introduce FIMPA, an integrated analytical framework for standardized, multi-parametric stroke evaluation based on NIR-II fluorescence perfusion imaging. FIMPA systematically processes the image sequence through motion correction and atlas registration to generate an anatomically aligned library of 125 vascular and hemodynamic parameters. Statistical screening identifies 67 stroke-correlated features, enabling objective, data-driven quantification of perfusion deficits. To resolve spatial infarct boundaries, we developed FIMPA-SI (FIMPA Stroke Index), a deep learning-based index utilizing a ViT-UNETR framework. By leveraging self-supervised pre-training with MRI data, FIMPA-SI suppresses dominant vascular signals to translate multi-parametric dynamics into anatomically precise stroke severity maps. Validated in tMCAO mice, FIMPA-SI achieves high spatial concordance with MRI and significantly outperforms conventional laser speckle contrast imaging and single-parameter metrics. FIMPA provides a robust solution for accelerating preclinical therapeutics and advancing optical neuroimaging.

Murine serine protease inhibitor clade A member 3N (SERPINA3N) and its human homolog SERPINA3 are injury-associated molecules induced in virtually all neurological conditions including ischemic stroke. Clinically, SERPINA3 is elevated in stroke patients, correlating with severe brain pathology and worse neurological outcomes. Yet, the exact cellular sources and therapeutic value of SERPINA3N/SERPINA3 in the ischemic brain remain elusive. Here, we report that oligodendrocytes are the major sources of SERPINA3/SERPINA3N and that SERPINA3N exerts neurotoxic effects in experimental cerebral ischemia. Given SERPINA3Ns secretory nature, we used knock-in Serpina3n-tdTom reporter mice to define its temporospatial evolution. The tdTom signal was barely detectable by day1 but gradually increased from day 3 through day 7 following cerebral ischemia. The majority of tdTom+ cells were identified as oligodendrocytes and astrocytes with fewer found in neurons or microglia. This cellular identity was corroborated by meta-analysis of single-cell transcriptomics datasets and human ischemic stroke brain data. Antagonizing SERPINA3N attenuated blood-brain barrier disruption, neuroinflammation, and neuronal damage and improved neurological function in a mouse model of cerebral ischemia. These findings resolve a longstanding debate regarding the cellular origins of SERPINA3N, identifying oligodendrocytes as its major source. Our studies highlight SERPINA3N antagonism as a possible therapeutic intervention for ischemic stroke, providing new insights for precision therapies that target oligodendroglia- or astroglia-specific SERPINA3N.

BACKGROUND AND PURPOSE: Measured intracranial vessel dimensions guide device selection in cerebrovascular intervention, yet accuracy depends on imaging modality, luminal contrast concentration, and the lumen-edge detection criteria. Prior accuracy studies benchmark one angiographic modality against another rather than physical ground truth. This study quantifies accuracy of CT angiography (CTA), 3D rotational angiography (3DRA), and 2D digital subtraction angiography (DSA) against a phantom of tubular contrast-filled structures serving as surrogates for intracranial vessels. MATERIALS AND METHODS: Phantoms with cylindrical lumen diameters 1.2-8.5 mm at graded iodinated contrast concentrations (6.25-100%) were imaged with clinical devices in air and a tissue-equivalent gel surround. Tubular cross-sections perpendicular to centerlines were measured by maximum-gradient, full-width-half-maximum (FWHM), and fixed-Hounsfield criteria and compared with physical phantom measurements using mixed-effects models. RESULTS: Across 1682 cross-sections (73 lumens), all modalities recovered true diameter within ~0.5 mm but consistently measured larger than the true dimensions. Over-measurement occurred minimally in the 2-5 mm range, maximally at the extremes of caliber and contrast concentration. 3DRA was modestly closer to physical phantom measurements than CTA (gradient bias +0.40 vs +0.60 mm). Maximum-gradient edge over-measured diameters versus the conventionally preferred FWHM, with the latter carrying larger, more concentration-sensitive bias. Fixed-HU thresholds were concentration-biased on CTA and unusable on 3DRA. 2D DSA, currently the clinical reference standard, was itself biased in analysis of its auto-calibrated measurements, over-measuring large lumens, under-measuring small lumens 1.5 mm, and reading larger frontally than laterally through magnification. CONCLUSIONS: Conventional CTA, 3DRA, and 2D DSA each measure intracranial-scale caliber lumens within ~0.5 mm but with consistent bias. Maximum-gradient lumen edge detection minimizes bias and outperforms FWHM, while fixed-Hounsfield contour tracing is unreliable, particularly on 3DRA. Characterizing these error modes provides a calibration basis for automated vessel-measurement platforms.

Background: Cardiovascular, kidney, and metabolic diseases are closely interconnected and may share common pathophysiological mechanisms, including microvascular dysfunction. Although cardiac 82Rb-PET/CT is routinely used for myocardial perfusion imaging, its potential for integrated cardio-renal perfusion assessment and cardiometabolic phenotyping remains underexplored. We recently developed a compartment modelling approach to quantify renal perfusion from routine cardiac 82Rb-PET/CT, enabling simultaneous assessment of cardio-renal perfusion. However, real-world imaging registries integrating these phenotypes with longitudinal clinical outcomes are lacking. Aim: To establish a real-world imaging registry that repurposes routine cardiac 82Rb-PET/CT by integrating PET-derived hemodynamic measures and CT-derived imaging biomarkers with detailed clinical, echocardiographic, laboratory, and clinical outcome data. Methods: The APOLLO registry is a single-centre retrospective registry of consecutive patients undergoing routine cardiac 82Rb-PET/CT at Alrijne Hospital (Leiderdorp, the Netherlands) between 2021-2023. Clinical, laboratory, medication, echocardiographic, and imaging data were collected to enable integrated cardio-renal perfusion assessment and cardiometabolic phenotyping. Inverse probability of selection weighting analysis was performed to account for renal coverage selection criteria. Cardiac perfusion was quantified using myocardial blood flow and myocardial flow reserve, while renal perfusion was derived using our previously developed compartment-model. Additional phenotyping included adiposity and frailty-related biomarkers, great vessel diameters, vascular calcification, diastolic dysfunction grading, H2FPEF score, Cardio-Kidney-Metabolic (CKM) staging, and longitudinal assessment of major adverse cardiovascular events. Conclusion: APOLLO registry extends routine cardiac 82Rb-PET/CT beyond myocardial perfusion imaging by integrating cardio-renal perfusion measurements with detailed cardiometabolic, clinical, and outcome phenotypes. This real-world registry provides a unique platform for future mechanistic and outcome-based research across the CKM disease spectrum.

Monoamine oxidase B (MAO-B) is a high-density protein located mainly in astrocytes that influences mitochondrial function and transition to astrogliosis. MAO-B produces hydrogen peroxide while metabolizing non-serotonergic monoamines. Elevated MAO-B level is implicated in the pathophysiology of several common neuropsychiatric diseases. The aims are to examine the effect of treatment resistant major depressive episodes, sex, and antidepressant treatment on MAO-B total distribution volume ([11C]SL25.1188 VT), index of MAO-B level. [11C]SL25.1188 PET was applied in 95 adults (29 with MDE and no history of treatment-resistance (NTR-MDE), 26 with MDE and history of treatment-resistance (TRD), and 40 healthy control (HC)). A subset of NTR-MDE and TRD (n=13) were scanned before and after treatment with phenelzine, rasagiline, or duloxetine. [11C]SL25.1188 VT was higher in grey matter regions in females (10%, p<.001). [11C]SL25.1188 VT was also higher in prefrontal cortex in TRD compared to HC (23%, p<.001) and TRD compared to NTR-MDE (6%, p=.033). Duloxetine had minimal effect on [11C]SL25.1188 VT, but occupancy of rasagiline and phenelzine was ~94%. This study discovered sex differences in MAO-B level, which may explain sex differences in prevalence or trajectory of illnesses with greater MAO-B level like Alzheimer's disease, traumatic brain injury and major depressive disorder. Given our findings of greater MAO-B level in prefrontal cortex of TRD and its insensitivity to serotonin reuptake inhibition, combined with potential harm of highly elevated MAO-B level, development of MAO-B inhibitors could be considered for a subset of TRD. Rasagiline and phenelzine demonstrate similarly potent occupancy in vivo at clinical dosage.

Background: Low-density lipoprotein cholesterol (LDL-C) is an established risk factor for atherosclerotic cerebrovascular disease, but its effects on the cerebral microcirculation are poorly defined. We investigated whether LDL-C is associated with pericyte dysfunction in acute ischemic stroke (AIS) and explored underlying mechanisms. Methods: Serum soluble platelet-derived growth factor receptor-{beta} (sPDGFR{beta}) was measured in two independent AIS cohorts (n=97 and n=86). Cerebral pericyte transcriptional responses to LDL-C were analyzed by single-cell RNA sequencing in Apoe-knockout mice fed control or high-fat diet (n=4 [male/female: 2/2]/group), and cultured human brain pericytes were exposed to purified human LDL cholesterol with or without N-acetyl-L-cysteine. Results: Higher serum sPDGFR{beta} was associated with greater neurological deficit and circulating neurofilament light chain. LDL-C positively correlated with sPDGFR{beta} in both clinical cohorts. High-fat diet induced coordinated suppression of type-I interferon pathways, and a positive shift in reactive oxygen species-related transcriptional programs in mouse pericytes; exploratory sex-by-diet analyses suggested larger transcriptional responses in females. In cultured human pericytes, LDL-C induced oxidative-stress, lipid-handling, and ferroptosis-associated transcriptional programs while suppressing type-I interferon signaling. Cross-species enrichment analysis showed that LDL-C-induced and -repressed signatures in cultured pericytes aligned with the sex-by-diet interaction in Apoe-knockout mice. LDL-C also reduced cell-surface PDGFR{beta} and increased sPDGFR{beta} release in cultured pericytes, which were significantly attenuated by N-acetyl-L-cysteine, whereas LDH activity increased numerically but not significantly. Conclusions: Clinical and experimental findings support an LDL-pericyte axis linking atherogenic lipid stress to cerebral microvascular dysfunction, with possible sex-dependent modulation of oxidative stress and type-I interferon signaling as potential mechanisms.

Purpose: Attenuation correction (AC) of PET images is essential for accurate quantification. Brain PET studies comprising simultaneous EEG (PETEEG) may suffer from metal artifacts in CT images (CTEEG), or improper correction when electrodes are not present in the CT (CT0). As these influences are not well-characterized, we aim to compare metal artifact reduction (MAR) techniques for CTEEG images, and evaluate differences between attenuated-corrected PETEEG using CT0 and CTEEG with MAR, synthetically placed electrodes (CTEEG-synth) and extended Hounsfield unit (HU) range. Methods: 19 healthy participants underwent two total-body PET/CT scans with [18F]FDG, with and without 32 EEG scalp electrodes, respectively. We evaluated five MARs to reduce streaks caused by the EEG electrodes in the CTEEG. Finally, CT0, CTEEG with (CTEEG-iMAR-Ext) and without extended HU range (CTEEG-iMAR) and CTEEG-synth were used to perform attenuation correction of PETEEG. We compared our results to PET0/CT0 scan using relative differences. Results: CTEEG and CTEEG-iMAR showed the smallest differences to CT0. PETEEG/CTEEG-iMAR-Ext exhibited the lowest differences to PET0/CT0 (average bias across all regions of -0.46%), followed by similar performance of PETEEG/CTEEG-iMAR (-0.73%) and PETEEG/CTEEG (-0.76%). Conversely, PETEEG/CT0 demonstrated the largest average differences (-1.81%), with values reaching -2.71% in the parietal lobe. These differences were consistent across subjects, yielding significant effects in most of the brain (pFWE < 0.05). CTEEG-synth performed not as good as CTEEG (-1.21%). Conclusions: CTEEG with extended HU range is most suitable for attenuation correction of PETEEG images, with MAR correction offering little additional improvement.

Functional near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI) both rely on the phenomenon of neurovascular coupling (NVC) to probe brain activity through their sensitivity to cerebral blood oxygenation. However, the relationship between fNIRS chromophores (oxy- and deoxyhaemoglobin, HbO and HbR), and fMRI (Blood Oxygen Level Dependent and Arterial Spin Labeling, BOLD and ASL) measurements, and whether this relationship remains consistent across subjects and physiological conditions, has only been partially characterised.. We acquired concurrent continuous-wave fNIRS and gradient-echo (GE) and spin-echo (SE) BOLD-ASL fMRI in healthy adults (n = 10) during visual stimulation. By applying calibrated fMRI methodology, we examined the relationships between fNIRS-derived haemoglobin modulations and fMRI-derived modulations in macrovascular (GE-) and microvascular (SE-) BOLD signals, cerebral blood flow (CBF), and oxygen metabolism (CMRO2). Group-level results showed strong temporal cross-modal agreement, with HbO and HbR tightly mirroring all fMRI signal time-courses (|r| > 0.8). A quantitative analysis of trial-by-trial modulations revealed distinct state-dependent behaviours: HbO maintained a stable relationship with the fMRI-derived metrics across conditions, whereas cross-modal relationships between HbR and fMRI-derived metrics substantially strengthened at higher flow-metabolism coupling (FMC), the ratio of CBF to CMRO2 change, an index of the strength of NVC. Both HbO and HbR were more strongly associated with GE-BOLD than with SE-BOLD. These findings provide a rigorous physiological grounding for fNIRS signal interpretation, demonstrating its utility as a surrogate marker for specific haemodynamic and metabolic parameters.

Background. Dynamic susceptibility contrast MRI with capillary-function post-processing exports a relative maximum cerebral metabolic rate of oxygen, formed from blood flow and a transit-time-derived extraction term. The share each contributes to an observed contrast is unquantified. Methods. In a retrospective single-centre cohort with untreated glioblastoma, six perfusion maps normalised to normal-appearing white matter were sampled in automatically segmented enhancing tumour and peritumoral brain. The paired compartment contrast in the oxygen-metabolism index was partitioned into flow, extraction and residual terms and examined against tumour-core volume. Results. Of 131 patients, 122 were analysable. Flow-linked maps were about twice as high in enhancing tumour, the transit and extraction maps only modestly (all q < 0.05). Flow accounted for 92.6% (95% CI 85.9-98.8) of the contrast and extraction for 6.6% (0.7-12.9). Across volume tertiles the flow share rose from 67.8% to 104.0%, a gradient arising peritumorally: every map changed with volume there, none in enhancing tumour. Conclusion. The compartment contrast in the oxygen-metabolism index is largely accounted for by blood flow and varies with lesion size, that dependence originating peritumorally. It should be read within the complete perfusion panel, not as independent metabolic evidence.

Background: Whether ethnoracial differences in cerebral small vessel disease (cSVD) appear in multimarker burden, particular MRI manifestations, or both, and how they relate to Life's Essential 8 (LE8) cardiovascular health and cognition, remain unclear. Methods: This cross-sectional study included 44,982 participants and an age- and sex-matched subsample of 1,426 with reviewed lacune and cerebral microbleed (CMB) ratings. White, South Asian, Black, Chinese and Mixed participants were compared on 0-2 (white matter hyperintensity [WMH]/enlarged perivascular space [ePVS]) and 0-4 (adding CMB and lacunes) composite scores and each marker. LE8 was related to WMH and composite burden, and cognitive means were compared by group. Models were age-, sex- and center-adjusted with false-discovery-rate correction. Results: Both composite scores differed across groups (0-2: P=0.00010; 0-4: P=0.0011), with greater burden in Black than South Asian (0-4: OR 1.66; 95% CI, 1.21-2.28) and Chinese participants (OR 2.36; 1.51-3.70), whereas Black-White contrasts were not detected. Black participants had higher WMH volume than White participants (=0.209; 0.110-0.308), robust to deprivation adjustment and segmentation method; South Asian participants had fewer ePVS (0.82; 0.72-0.93). No ethnoracial-group differences in lacune or CMB counts were detected after correction. Higher LE8 was associated with lower WMH volume (0.13 per SD; 0.17 to 0.09) and lower two-marker burden (OR 0.89 per SD; 0.87-0.91) without detected ethnoracial moderation. Black participants, who had the least favorable LE8 scores, and South Asian participants had lower global cognition than White participants (z 0.76 and 0.57 versus 0.24) despite differing WMH profiles; the pooled WMH-cognition association was null. Conclusions: Ethnoracial differences in multimarker cSVD burden were evident but marker-dependent: WMH showed the clearest Black-White difference; focal-lesion contrasts were inconclusive. Better cardiovascular health related to lower WMH and aggregate cSVD burden across groups, whereas cognitive differences did not track cSVD burden, supporting prospective prevention and cognition studies.

BACKGROUND: White matter hyperintensities (WMHs), the principal imaging manifestation of cerebral small vessel disease, lack an animal model that produces pathology of sufficient magnitude to validate potential therapeutics. We characterized white matter (WM) degeneration in a renovascular hypertension (RVH) rat model, interrogated its mechanism, and tested its relevance in patients. METHODS: RVH was induced by two-kidney, two-clip surgery and assessed by T2-weighted and diffusion MRI, myelin and axonal histology, and blood-brain barrier (BBB) leakage markers. The influence of angiotensin II (Ang II) on barrier function in brain endothelial cells was examined using transendothelial electrical resistance and reactive oxygen species (ROS) assays. Losartan was infused intracerebroventricularly to block brain AT1R (Ang II type 1 receptor) without systemic blood pressure reduction. WMH burden was compared between patients with and without renal artery stenosis, and WMH progression across antihypertensive classes was assessed in the CHALLENGE (Korea), MSS2 (UK), LBC1936 (UK), and SPRINT-MIND-MRI (US) cohorts. RESULTS: Approximately two-thirds of RVH rats developed WMHs that expanded between 7 and 9 weeks, accompanied by reduced fractional anisotropy, demyelination, axonal and mature oligodendrocyte loss, and glial activation. IgG, albumin, and fibrinogen leakage was confined to affected WM. Ang II impaired endothelial barrier function and generated ROS through AT1R. Intracerebroventricular losartan attenuated WM pathology and improved behavior while blood pressure remained comparably elevated. Patients with renal artery stenosis had higher WMH volumes (10.52 versus 6.52 mL; P = 0.035). Angiotensin receptor blocker use was associated with the slowest tertile of annual WMH progression in the Korean cohort (OR, 2.57 [95% CI, 1.20-5.61]) and among White participants in SPRINT-MIND-MRI (OR, 3.52 [95% CI, 1.05-12.29]). CONCLUSIONS: RVH produces prominent ischemic WM degeneration driven by AT1R signaling, identifying a blood pressure-independent therapeutic target with corroborating clinical evidence.

Apolipoprotein E4 (E4) increases the risk of Alzheimers disease (AD) by up to 12-fold. However, understanding of the mechanisms underlying this increased risk has been limited by a lack of preclinical models that accurately reflect the effects of E4 in the presence of humanized non-mutant amyloid-{beta} precursor protein (hA{beta}PP). Therefore, we studied novel humanized APOE and hA{beta}PP mice to investigate the contributions of the E4 genotype to cognitive, inflammatory, and vascular dysfunction, specifically comparing male and female E3/hA{beta}PP and E4/hA{beta}PP mice. E4/hA{beta}PP mice exhibited impaired nest-building behavior and novel object recognition compared with E3/hA{beta}PP mice. Microglial content was higher in E4/hA{beta}PP mice, whereas astrocyte content was not different across groups. E4/hA{beta}PP mice had greater carotid and cerebral artery stiffness, and higher collagen I content in cerebral arteries than E3/hA{beta}PP mice. Under static pressure, cerebral artery endothelium-dependent and endothelium-independent vasodilation were similar across genotypes. However, high pulse pressure selectively impaired cerebral artery endothelial function in E4/hA{beta}PP mice, with the greatest impairment observed in females. The E4/hA{beta}PP mice also exhibited higher cortical expression of Nox2 and Sod1 and elevated cerebral artery Il1b expression. As such, E4/hA{beta}PP mice exhibit convergent cognitive, inflammatory, and vascular abnormalities that recapitulate several features of AD. Elevated pulse pressure revealed an E4-dependent vulnerability of the cerebral vasculature, suggesting that vascular stress may be an important contributor to disease risk. Together, our findings support the use of the APOExhA{beta}PP model to investigate the mechanisms by which E4 promotes vascular dysfunction, neuroinflammation, and cognitive impairment in AD.

Rationale: Thrombi are fragile, heterogeneous, and difficult to study with available methods, yet understanding their molecular composition and local microenvironment in stroke is critical to elucidating stroke pathophysiology and improving patient outcomes. Objective: We used a novel platform for harvesting and analyzing intracranial thrombi from endovascular thrombectomy for large vessel occlusion to define the cellular and transcriptomic landscape of thrombi. Methods and results: We performed single-nuclei RNA sequencing (snRNA-seq) on three human intracranial thrombi to define their molecular composition and microenvironment. Across 5,143 nuclei, we identified 8 distinct cellular populations, including monocytes and T cells. Monocytes displayed transcriptional changes on gene and regulon levels suggestive of transdifferentiation. We integrated our snRNA-seq data with publicly available single cell RNA-sequencing (scRNA-seq) data from asymptomatic and symptomatic atherosclerotic carotid plaques, and scRNA-seq data from healthy brain vasculature. We identified shared transcriptional programs between carotid and thrombi monocytes along dimensions including inflammation and endothelial activation, supporting the notion that thrombi monocytes undergo transdifferentiation in stroke. We also inferred potential ligand-receptor interactions that may occur at the site and time of occlusion. Conclusion: Our novel application of snRNA-seq to thrombectomy specimens has allowed us to uncover the full diversity of cell types present in thrombi, including low-abundance and novel cell populations, and to provide evidence of cellular plasticity and intercellular communication at the site of occlusion. This detailed definition of the cellular populations involved in stroke will facilitate mapping of novel interventional targets with direct functional relevance and facilitate greater personalization of post-reperfusion therapy.