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OBJECTIVE: Abnormal tumor vascular network contributes to aberrant blood perfusion and reduced oxygenation in tumors, which lead to poor efficacy of chemotherapy and radiotherapy. We aimed to explore the effects of the tumor-derived exosomes (TDEs) and C188-9 (a small molecule inhibitor of signal transducer and activator of transcription 3, STAT3) on tumor microvascular hemodynamics and determine which blood flow oscillations for various frequency intervals are responsible for these changes. METHODS: Microvascular hemodynamics parameters were recorded using a PeriFlux 6000 EPOS system in tumor surface in a nude mouse subcutaneous xenograft model. Oscillations of laser Doppler flowmetry (LDF) signal were investigated by wavelet transform analysis. RESULTS: TDEs facilitated tumor growth at least partially was associated with increasing blood flow in smaller vessels with lower speed and decreasing the blood flow at larger vessels with higher speed. Lower oxyhemoglobin saturation (SO2) on tumor surface was aggravated by TDEs, and C188-9 treatment significantly alleviated this decrease. Wavelet transform spectral analysis revealed that TDEs increased the amplitude of oscillations in four frequency intervals related to endothelial (NO-dependent and -independent), myogenic and neurogenic activities, and C188-9 had no effect on this increase. CONCLUSIONS: TDEs facilitated tumor growth partially was associated with increasing blood flow in distributing vessels, reducing blood perfusion in larger vessels, and lowering SO2 on tumor surface. Enhanced vascular smooth muscle, endothelial and neurogenic activities occurred in tumor superficial zone.

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BACKGROUND: Flowmotion analysis of the microcirculatory blood flow is a method to extract information about the vessel regulatory function. It has previously shown promise when applied to measurements during a post-occlusive reactive hyperemia. However, the reperfusion peak and the following monotonic decline introduces false low frequencies that should not be interpreted as rhythmic vasomotion effect. AIM: To develop and validate a robust method for flowmotion analysis of post-occlusive reactive hyperemia signals. METHOD: The occlusion-induced reperfusion response contains a typical rapid increase followed by a monotonic decline to baseline. A mathematical model is proposed to detrend this transient part of the signal to enable further flowmotion analysis. The model is validated in 96 measurements on healthy volunteers. RESULTS: Applying the proposed model corrects the flowmotion signal without adding any substantial new false flowmotion components. CONCLUSION: Future studies should use the proposed method or equivalent when analyzing flowmotion during post-occlusive reactive hyperemia to ensure valid results.

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This study investigated the impact of a multiday heatwave on nocturnal physiology, behavior, and sleep under controlled conditions with comprehensive monitoring of environmental factors and participant activities. Seven young healthy males were confined for 10 days in controlled conditions that ranged between hot-to-warm (day: 35.4 °C, night: 26.3 °C) during nights 4-6 and temperate (day: 25.4 °C, night: 22.3 °C) before (nights 1-3) and after (nights 7-10) the heatwave. Measurements included core and skin temperatures, heart rate, sympathovagal balance, vasomotion indicators, urine samples, blanket coverage, subjective sleep assessments, and partial polysomnography. The average nocturnal core temperature was 0.2 °C higher during and after the heatwave compared to the pre-heatwave period, with this difference being more pronounced (+0.3 °C) in the first 2 h of sleep (p < 0.001). For every 0.1 °C rise in overnight core temperature, the total sleep time decreased by 14 min (pseudo-R2 = 0.26, p = 0.01). The elevated core temperatures occurred despite the participants exhibiting evident thermoregulatory behavior, as they covered 30% less body surface during the heatwave compared to pre- and post-heatwave periods (p < 0.001). During the heatwave, mean skin temperature at bedtime was 1.3 °C higher than pre-heatwave and 0.8 °C higher than post-heatwave periods (p < 0.001). No differences in other responses, including heart rate and vasomotion indicators, were observed. The paper details a 20-min sleepwalking episode that was coupled with marked changes in sleepwalker's thermophysiological responses. In conclusion, the simulated heatwave resulted in higher overnight core temperature which was associated with reduced total sleep time. Behavioral thermoregulation during sleep may serve as a defense against these effects, though more research is needed.

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Background: It is not known whether the transition from obesity and severe obesity, as 2 different metabolic disease entities, affect flow-mediated and, thus, endothelium-dependent epicardial vasodilation. Objectives: The purpose of this study was to investigate the effect of obesity and severe obesity on flow-mediated epicardial vasomotion with positron emission tomography/computed tomography-determined longitudinal decrease in myocardial blood flow (MBF) from the base-to-apex direction of the left ventricle or gradient. Methods: 13N-ammonia positron emission tomography/computed tomography evaluated global MBF during pharmacologically induced hyperemia and at rest for assessment of coronary microvascular function. In addition, the Δ longitudinal MBF gradient (hyperemia minus rest) was determined. Patients were then grouped according to the body mass index (BMI) into normal weight (NW) (BMI 20.0-24.9 kg/m2, n = 27), overweight (OW) (BMI 25.0-29.9 kg/m2, n = 29), obesity (OB) (BMI 30.0-39.9 kg/m2, n = 53), and severe obesity (morbid obesity: BMI ≥40 kg/m2, n = 43). Results: Compared to NW, left ventricular Δ longitudinal MBF gradient progressively declined in OW and OB (0.04 ± 0.09 mL/g/min vs -0.11 ± 0.14 mL/g/min and -0.15 ± 0.11 mL/g/min; P ≤ 0.001, respectively) but not significantly in SOB (-0.01 ± 0.11 mL/g/min, P = 0.066). Regadenoson-induced global hyperemic MBF was lower in OB than in NW (1.88 ± 0.40 mL/g/min vs 2.35 ± 0.32 mL/g/min; P ≤ 0.001), while comparable between NW and SOB (2.35 ± 0.32 mL/g/min vs 2.26 ± 0.40 mL/g/min; P = 0.302). The BMI of the study population was associated with the Δ longitudinal MBF gradient in a U-turn fashion (r = 0.362, standard error of the estimate = 0.124; P < 0.001). Conclusions: Increased body weight associates with abnormalities in coronary circulatory function that advances from an impairment flow-mediated, epicardial vasodilation in overweight and obesity to coronary microvascular dysfunction in obesity, not observed in severe obesity. The U-turn of flow-mediated epicardial vasomotion outlines obesity and severe obesity to affect epicardial endothelial function differently.

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Bioresorbable stents represent a revolutionary treatment for coronary artery disease. Such a device offers the prospect for complete naturalization of artery lumen after strut resorption and restoration of vasomotion while curtailing the duration of dual anti-platelet therapy. The prototype bioresorbable scaffold (BRS-ABSORB GT1) demonstrated good feasibility and safety in the initial studies compared to metallic drug eluting stent but later fell out of favor due to multiple report of stent thrombosis and target lesion failure. Unpredictable resorption of struts turned out to be one of the "Achilles heel" of the BRS and stent strut were still visible in vessel on optical coherence tomography (OCT) at 3 years. We report a case of differential resorption of two ABSORB BRS implanted simultaneously in the same patient by the same operator. Follow up coronary angiogram revealed only minimal plaques on right coronary artery (RCA) and left anterior descending artery (LAD). The BRS were identified on cine-angiogram by their radio-opaque markers at both ends. The OCT run in LAD artery revealed "ghost remnants" of BRS struts in LAD, whereas the RCA BRS had completely healed with minimal "ghost" struts. The ghost remnants of BRS resembled the original "Check box" appearance on OCT during the index implantation.

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Background: Erectile dysfunction (ED) most often has vascular etiology and usually is the earliest symptom of vascular dysfunction. The aim of this study was to evaluate vascular dysfunction with the use of the Flow-Mediated Skin Fluorescence (FMSF) technique in men with and without ED. Methods: Included were 39 men (median age 53) with ED and 40 men (median age 41.5) without ED. Medical interview, physical examination, and anthropometrical measurements were performed for all participants. The serum total testosterone, LH, and SHBG determinations were performed in patients with ED, and the Free Testosterone Index (FTI) was calculated. The FMSF technique was used to measure the microcirculatory oscillations at the baseline and to determine the flowmotion (FM) and vasomotion (VM) parameters. The Normoxia Oscillatory Index (NOI) was calculated, which represents the contribution of the endothelial (ENDO) and neurogenic (NEURO) oscillations relative to all oscillations detected at low-frequency intervals (<0.15 Hz): NOI = (ENDO + NEURO)/(ENDO + NEURO + VM). Results: In men with ED were found significantly lower FM and VM parameters, but the NOI was significantly higher in comparison to men without ED. VM and FM correlated significantly positively with erectile function, orgasmic function, and general sexual satisfaction in the whole group and the FTI in the ED group. The thresholds of 53.5 FM (AUC = 0.7) and 8.4 VM (AUC = 0.7) were predictive values for discriminating men with ED. Conclusions: It was shown that the FMSF diagnostic technique may be helpful in the early diagnosis of microcirculation dysfunction due to impaired vasomotion caused by decreased testosterone activity.

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Spontaneous cerebral vasomotion, characterized by ∼0.1 Hz rhythmic contractility, is crucial for brain homeostasis. However, our understanding of vasomotion is limited due to a lack of high-precision analytical methods to determine single vasomotion events at basal levels. Here, we developed a novel strategy that integrates a baseline smoothing algorithm, allowing precise measurements of vasodynamics and concomitant Ca2+ dynamics in mouse cerebral vasculature imaged by two-photon microscopy. We identified several previously unrecognized vasomotion properties under different physiological and pathological conditions, especially in ischemic stroke, which is a highly harmful brain disease that results from vessel occlusion. First, the dynamic characteristics between SMCs Ca2+ and corresponding arteriolar vasomotion are correlated. Second, compared to previous diameter-based estimations, our radius-based measurements reveal anisotropic vascular movements, enabling a more precise determination of the latency between smooth muscle cell (SMC) Ca2+ activity and vasoconstriction. Third, we characterized single vasomotion event kinetics at scales of less than 4 seconds. Finally, following pathological vasoconstrictions induced by ischemic stroke, vasoactive arterioles entered an inert state and persisted despite recanalization. In summary, we developed a highly accurate technique for analyzing spontaneous vasomotion, and our data suggested a potential strategy to reduce stroke damage by promoting vasomotion recovery.

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The presence of global synchronization of vasomotion induced by oscillating visual stimuli was identified in the mouse brain. Endogenous autofluorescence was used and the vessel 'shadow' was quantified to evaluate the magnitude of the frequency-locked vasomotion. This method allows vasomotion to be easily quantified in non-transgenic wild-type mice using either the wide-field macro-zoom microscopy or the deep-brain fiber photometry methods. Vertical stripes horizontally oscillating at a low temporal frequency (0.25 Hz) were presented to the awake mouse, and oscillatory vasomotion locked to the temporal frequency of the visual stimulation was induced not only in the primary visual cortex but across a wide surface area of the cortex and the cerebellum. The visually induced vasomotion adapted to a wide range of stimulation parameters. Repeated trials of the visual stimulus presentations resulted in the plastic entrainment of vasomotion. Horizontally oscillating visual stimulus is known to induce horizontal optokinetic response (HOKR). The amplitude of the eye movement is known to increase with repeated training sessions, and the flocculus region of the cerebellum is known to be essential for this learning to occur. Here, we show a strong correlation between the average HOKR performance gain and the vasomotion entrainment magnitude in the cerebellar flocculus. Therefore, the plasticity of vasomotion and neuronal circuits appeared to occur in parallel. Efficient energy delivery by the entrained vasomotion may contribute to meeting the energy demand for increased coordinated neuronal activity and the subsequent neuronal circuit reorganization.

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Accumulating evidence shows that most chronic neurological diseases have a link with sleep disturbances, and that patients with chronically poor sleep undergo an accelerated cognitive decline. Indeed, a single-night of sleep deprivation may increase metabolic waste levels in cerebrospinal fluid. However, it remains unknown how chronic sleep disturbances in isolation from an underlying neurological disease may affect the glymphatic system. Clearance of brain interstitial waste by the glymphatic system occurs primarily during sleep, driven by multiple oscillators including arterial pulsatility, and vasomotion. Herein, we induced sleep fragmentation in young wildtype mice and assessed the effects on glymphatic activity and cognitive functions. Chronic sleep fragmentation reduced glymphatic function and impaired cognitive functions in healthy mice. A mechanistic analysis showed that the chronic sleep fragmentation suppressed slow vasomotion, without altering cardiac-driven pulsations. Taken together, results of this study document that chronic sleep fragmentation suppresses brain metabolite clearance and impairs cognition, even in the absence of disease.

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Vasomotion refers to the spontaneous oscillation of blood vessels within a frequency range of 0.01 to 1.6 Hz. Various disease states, including hypertension and diabetes, have been associated with alterations in vasomotion at the finger, indicating potential impairment of skin microcirculation. Due to the non-linear nature of human vasculature, the modification of vasomotion may vary across different locations for different diseases. In this study, Laser Doppler Flowmetry was used to measure blood flow motion at acupoints LU8, LU5, SP6, and PC3 among 49 participants with or without diabetes and/or hypertension. Fast Fourier Transformation was used to analyze noise type while Hilbert-Huang Transformation and wavelet analysis were applied to assess Signal Noise Ratio (SNR) results. Statistical analysis revealed that different acupoints exhibit distinct spectral characteristics of vasomotion not only among healthy individuals but also among patients with diabetes and/or hypertension. The results showed strong heterogeneity of vasomotion among blood vessels, indicating that the vasomotion measured at a certain point may not reflect the real status of microcirculation.

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Vasomotion is the oscillation of vascular tone which gives rise to flow motion of blood into an organ. As is well known, spontaneous contractile organs such as heart, GI, and genitourinary tract produce rhythmic contraction. It imposes or removes pressure on their vessels alternatively for exchange of many substances. It was first described over 150 years ago, however the physiological mechanism and pathophysiological implications are not well understood. This study aimed to elucidate underlying mechanisms and physiological function of vasomotion in human arteries. Conventional contractile force measurement, immunohistochemistry, and Western blot analysis were employed to study human left gastric artery (HLGA) and uterine arteries (HUA). RESULTS: Circular muscle of HLGA and/or HUA produced sustained tonic contraction by high K+ (50 mM) which was blocked by 2 µM nifedipine. Stepwise stretch and high K+ produced nerve-independent spontaneous contraction (vasomotion) (around 45% of tested tissues). Vasomotion was also produced by application of BayK 8644, 5-HT, prostagrandins, oxytocin. It was blocked by nifedipine (2 µM) and blockers of intracellular Ca2+ stores. Inhibitors of Ca2+ -activated Cl- channels (DIDS and/or niflumic acid) and ATP-sensitive K+ (KATP ) channels inhibited vasomotion reversibly. Metabolic inhibition by sodium cyanide (NaCN) and several neuropeptides also regulated vasomotion in KATP channel-sensitive and -insensitive manner. Finally, we identified TMEM16A Ca2+ -activated Cl- channels and subunits of KATP channels (Kir 6.1/6.2 and sulfonylurea receptor 2B [SUR2B]), and c-Kit positivity by Western blot analysis. We conclude that vasomotion is sensitive to TMEM16A Ca2+ -activated Cl- channels and metabolic changes in human gastric and uterine arteries. Vasomotion might play an important role in the regulation of microcirculation dynamics even in pacemaker-related autonomic contractile organs in humans.

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Chronic pain is a prevalent condition affecting approximately one-fifth of the global population, with significant impacts on quality of life and work productivity. Small fiber neuropathies are a common cause of chronic pain, and current diagnostic methods rely on subjective self-assessment or invasive skin biopsies, highlighting the need for objective noninvasive assessment methods. The study aims to develop a modular prototype of a contactless photoplethysmography system with three spectral bands (420, 540, and 800 nm) and evaluate its potential for assessing peripheral neuropathy patients via a skin topical heating test and spectral analyses of cutaneous flowmotions. The foot topical skin heating test was conducted on thirty volunteers, including fifteen healthy subjects and fifteen neuropathic patients. Four cutaneous nerve fiber characterizing parameters were evaluated at different wavelengths, including vasomotor response trend, flare area, flare intensity index, and the spectral power of cutaneous flowmotions. The results show that neuropathic patients had significantly lower vasomotor response (50%), flare area (63%), flare intensity index (19%), and neurogenic component (54%) of cutaneous flowmotions compared to the control group, independent of photoplethysmography spectral band. An absolute value of perfusion was 20%-30% higher in the 420 nm band. Imaging photoplethysmography shows potential as a cost-effective alternative for objective and non-invasive assessment of neuropathic patients, but further research is needed to enhance photoplethysmography signal quality and establish diagnostic criteria.

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Pancreatic islets are endocrine organs that depend on their microvasculature to function. Along with endothelial cells, pericytes comprise the islet microvascular network. These mural cells are crucial for microvascular stability and function, but it is not known if/how they are affected during the development of type 1 diabetes (T1D). Here, we investigate islet pericyte density, phenotype, and function using living pancreas slices from donors without diabetes, donors with a single T1D-associated autoantibody (GADA+), and recent onset T1D cases. Our data show that islet pericyte and capillary responses to vasoactive stimuli are impaired early on in T1D. Microvascular dysfunction is associated with a switch in the phenotype of islet pericytes toward myofibroblasts. Using publicly available RNA sequencing (RNA-seq) data, we further found that transcriptional alterations related to endothelin-1 signaling and vascular and extracellular matrix (ECM) remodeling are hallmarks of single autoantibody (Aab)+ donor pancreata. Our data show that microvascular dysfunction is present at early stages of islet autoimmunity.

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Vascular factors are known to be early and important players in Alzheimer's disease (AD) development, however the role of the ε4 allele of the Apolipoprotein (APOE) gene (a risk factor for developing AD) remains unclear. APOE4 genotype is associated with early and severe neocortical vascular deficits in anaesthetised mice, but in humans, vascular and cognitive dysfunction are focused on the hippocampal formation and appear later. How APOE4 might interact with the vasculature to confer AD risk during the preclinical phase represents a gap in existing knowledge. To avoid potential confounds of anaesthesia and to explore regions most relevant for human disease, we studied the visual cortex and hippocampus of awake APOE3 and APOE4-TR mice using 2-photon microscopy of neurons and blood vessels. We found mild vascular deficits: vascular density and functional hyperaemia were unaffected in APOE4 mice, and neuronal or vascular function did not decrease up to late middle-age. Instead, vascular responsiveness was lower, arteriole vasomotion was reduced and neuronal calcium signals during visual stimulation were increased. This suggests that, alone, APOE4 expression is not catastrophic but stably alters neurovascular physiology. We suggest this state makes APOE4 carriers more sensitive to subsequent insults such as injury or beta amyloid accumulation.

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BACKGROUND: Post-occlusive reactive hyperemia (PORH) test with signal spectral analysis coupled provides potential indicators for the assessment of microvascular functions. OBJECTIVE: The objective of this study is to investigate the variations of skin blood flow and temperature spectra in the PORH test. Furthermore, to quantify the oscillation amplitude response to occlusion within different frequency ranges. MATERIALS AND METHODS: Ten healthy volunteers participated in the PORH test and their hand skin temperature and blood flow images were captured by infrared thermography (IRT) and laser speckle contrast imaging (LSCI) system, respectively. Extracted signals from selected areas were then transformed into the time-frequency space by continuous wavelet transform for cross-correlation analysis and oscillation amplitude response comparisons. RESULTS: The LSCI and IRT signals extracted from fingertips showed stronger hyperemia response and larger oscillation amplitude compared with other areas, and their spectral cross-correlations decreased with frequency. According to statistical analysis, their oscillation amplitudes in the PORH stage were obviously larger than the baseline stage within endothelial, neurogenic, and myogenic frequency ranges (p < 0.05), and their quantitative indicators of oscillation amplitude response had high linear correlations within endothelial and neurogenic frequency ranges. CONCLUSION: Comparisons of IRT and LSCI techniques in recording the reaction to the PORH test were made in both temporal and spectral domains. The larger oscillation amplitudes suggested enhanced endothelial, neurogenic, and myogenic activities in the PORH test. We hope this study is also significant for investigations of response to the PORH test by other non-invasive techniques.

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Introduction: Small animal fMRI is an essential part of translational research in the cognitive neurosciences. Due to small dimensions and animal physiology preclinical fMRI is prone to artifacts that may lead to misinterpretation of the data. To reach unbiased translational conclusions, it is, therefore, crucial to identify potential sources of experimental noise and to develop correction methods for contributions that cannot be avoided such as physiological noise. Aim of this study was to assess origin and prevalence of hemodynamic oscillations (HDO) in preclinical fMRI in rat, as well as their impact on data analysis. Methods: Following the development of algorithms for HDO detection and suppression, HDO prevalence in fMRI measurements was investigated for different anesthetic regimens, comprising isoflurane and medetomidine, and for both gradient echo and spin echo fMRI sequences. In addition to assessing the effect of vasodilation on HDO, it was studied if HDO have a direct neuronal correlate using local field potential (LFP) recordings. Finally, the impact of HDO on analysis of fMRI data was assessed, studying both the impact on calculation of activation maps as well as the impact on brain network analysis. Overall, 303 fMRI measurements and 32 LFP recordings were performed in 71 rats. Results: In total, 62% of the fMRI measurements showed HDO with a frequency of (0.20 ± 0.02) Hz. This frequent occurrence indicated that HDO cannot be generally neglected in fMRI experiments. Using the developed algorithms, HDO were detected with a specificity of 95%, and removed efficiently from the signal time courses. HDO occurred brain-wide under vasoconstrictive conditions in both small and large blood vessels. Vasodilation immediately interrupted HDO, which, however, returned within 1 h under vasoconstrictive conditions. No direct neuronal correlate of HDO was observed in LFP recordings. HDO significantly impacted analysis of fMRI data, leading to altered cluster sizes and F-values for activated voxels, as well as altered brain networks, when comparing data with and without HDO. Discussion: We therefore conclude that HDO are caused by vasomotion under certain anesthetic conditions and should be corrected during fMRI data analysis to avoid bias.

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Background: The regulation of microcirculation depends on the dynamic interaction of different factors: the autonomic nervous system plays a pivotal role in the blood flow and acupuncture can modulate it, obtaining different results depending on the site, the frequency, and the intensity of the stimulation. Methods: 18 healthy subjects have been enrolled and have undergone two sessions of electroacupuncture stimulations: one session using high frequency and one with low frequency. Microcirculation has been monitored continuously during stimulation using the laser Doppler method. Results: The microcirculatory parameters have shown a significant difference between high and low-frequency stimulation, suggesting that low-frequency stimulation is more effective for obtaining a vasodilator effect. Discussion: Our results show that low-frequency stimulation can increase the cutaneous microcirculatory flux, without significantly modifying blood pressure and heart rate. The auricular stimulation causes an increase in the activity of the vagus nerve, increasing the cholinergic activity without acting on post-junctional muscarinic receptors. Conclusion: Auricular acupuncture has a significant impact on the regulation of microcirculation.

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INTRODUCTION: Coronary vasomotion disorders (CVDs), including microvascular angina (MVA) and vasospastic angina (VSA), account for significant morbidity among patients with non-obstructive coronary artery disease (NOCAD). However, protocols for CVD assessment in clinical practice are seldom standardized and may be difficult to implement. PURPOSE: To assess the safety and feasibility of a comprehensive coronary function test (CFT) protocol for assessment of CVD and the prevalence of different phenotypes of CVD in patients with angina and NOCAD (ANOCA). METHODS: Patients with persistent angina referred for invasive coronary angiogram and found to have NOCAD were prospectively recruited and underwent a CFT. Functional parameters (fractional flow reserve, coronary flow reserve and index of myocardial resistance) and coronary vasoreactivity were assessed in all patients. RESULTS: Of the 20 patients included, the mean age was 63±13 years and 50% were females. Most patients had persistent typical angina and evidence of ischemia in noninvasive tests (75%). The CFT was successfully performed in all subjects without serious complications. Isolated MVA was found in 25%, isolated VSA in 40%, both MVA and VSA in 10% and noncardiac chest pain in 25% of patients. Antianginal therapy was modified after the results of CFT in 70% of patients. CONCLUSION: A coronary function test was feasible and safe in a cohort of patients with ANOCA. CVD were prevalent in this selected group of patients, and some presented mixed CVD phenotypes. CFT may provide a definitive diagnosis in patients with persistent angina and prompt the stratification of pharmacological therapy.

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Sensory stimulation evokes a local, vasodilation-mediated blood flow increase to the activated brain region, which is referred to as functional hyperemia. Spontaneous vasomotion is a change in arteriolar diameter that occurs without sensory stimulation, at low frequency (∼0.1 Hz). These vessel diameter changes are a driving force for perivascular soluble waste clearance, the failure of which has been implicated in neurodegenerative disease. Stimulus-evoked vascular reactivity is known to propagate along penetrating arterioles to pial arterioles, but it is unclear whether spontaneous vasomotion propagates similarly. We therefore imaged both stimulus-evoked and spontaneous changes in pial arteriole diameter in awake, head-fixed mice with 2-photon microscopy. By cross-correlating different regions of interest (ROIs) along the length of imaged arterioles, we assessed vasomotion propagation. We found that both during rest and during visual stimulation, one-third of the arterioles showed significant propagation (i.e., a wave), with a median (interquartile range) wave speed of 405 (323) µm/s at rest and 345 (177) µm/s during stimulation. In a second group of mice, with GCaMP expression in their vascular smooth muscle cells, we also found spontaneous propagation of calcium signaling along pial arterioles. In summary, we demonstrate that spontaneous vasomotion propagates along pial arterioles like stimulus-evoked vascular reactivity.

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Cerebrovascular dysfunction has been suggested as a physiomarker of Alzheimer's disease (AD)-associated neuronal degeneration, but the underlying mechanisms are still debated. Herein cerebral vasomotor reactivity (VMR, breath-hold index: BHI), metabolic activity (lobar SUVs, FDG PET MRI), amyloid load (Centiloid score, Flutemetamol PET MRI), hemispheric cortical thickness, white matter lesion load and cerebral blood flow (ASL) were studied in 43 consecutive subjects (mean age: 64 years, female 13), diagnosed with subjective cognitive impairment (SCI, n = 10), amnestic mild cognitive impairment (aMCI, n = 15), and probable Alzheimer's dementia (AD, n = 18). BHI was significantly reduced in AD and aMCI patients compared to SCI subjects. A highly significant inverse correlation was found between BHI and the centiloid score (r = -0.648, p < 0.001). There was moderate positive correlation between BHI and frontal, temporal and parietal FDG SUV and ASL values, and a borderline negative correlation with age and white matter lesion volume. The link between amyloid burden and VMR was independent and strong in linear regression models where all these parameters were included (ß from -0.580 to -0.476, p < 0.001). In conclusion, our study confirms the negative association of cerebral amyloid accumulation and vasomotor reactivity in Alzheimer's disease with the most direct data to date in humans.

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