Process validation and preclinical development of a new PET cerebral blood flow tracer [11C]MMP for initial clinical trials.

BACKGROUND: 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is commonly used for diagnosis of dementia because brain glucose metabolism reflects neuronal activity. However, as [18F]FDG is an analogue of glucose, accumulation of tracer in the brain is affected by plasma glucose levels. In contrast, cerebral blood flow (CBF) tracers are theoretically unaffected by plasma glucose levels and are therefore expected to be useful alternatives for the diagnosis of dementia in patients with diabetes. The techniques currently used for CBF imaging using single photon emission computed tomography (SPECT) and [15O]H2O positron emission tomography (PET), but these are limited by their insufficient resolution and sensitivity for regional brain imaging, especially in patients with brain atrophy. N-isopropyl-4-[11C]methylamphetamine ([11C]MMP) is a possible CBF tracer with high resolution and sensitivity that exhibits comparable performance to that of [15O]H2O in conscious monkey brains. We performed process validation of the radiosynthesis and preclinical development of [11C]MMP prior to clinical translation. RESULTS: The decay-corrected yields of [11C]MMP at the end of synthesis were 41.4 ± 6.5%, with 99.7 ± 0.3% radiochemical purity, and 192.3 ± 22.5 MBq/nmol molar activity. All process validation batches complied with the product specifications. The acute toxicity of MMP was evaluated at a dose of 3.55 mg/kg body weight, which is 10,000 times the potential maximum clinical dose of [11C]MMP. The acute toxicity of [11C]MMP injection at 150 or 200 times, to administer a postulated dose of 740 MBq of [11C]MMP, was also evaluated after the decay-out of 11C. No acute toxicity of MMP and [11C]MMP injection was found. No mutagenic activity was observed for MMP. The effective dose calculated according to the Medical Internal Radiation Dose (MIRD) method was 5.4 µSv/MBq, and the maximum absorbed dose to the bladder wall was 57.6 µGy/MBq. MMP, a derivative of phenylalkylamine, showed binding to the sigma receptor, but had approximately 1/100 of the affinity of existing sigma receptor imaging agents. The affinity for other brain neuroreceptors was low. CONCLUSIONS: [11C]MMP shows acceptable pharmacological safety at the dose required for adequate PET imaging. The potential risk associated with [11C]MMP PET imaging is well within the acceptable dose limit.

Altered oxidative neurometabolic response to methylene blue in bipolar disorder revealed by quantitative neuroimaging.

BACKGROUND: Cerebral mitochondrial and hemodynamic abnormalities have been implicated in Bipolar Disorder pathophysiology, likely contributing to neurometabolic vulnerability-leading to worsen clinical outcomes and mood instability. To investigate neurometabolic vulnerability in patients with BD, we combined multi-modal quantitative MRI assessment of cerebral oxygenation with acute administration of Methylene Blue, a neurometabolic/hemodynamic modulator acting on cerebral mitochondria. METHODS: Fifteen euthymic patients with chronic BD-type 1, and fifteen age/gender-matched healthy controls underwent two separate MRI sessions in a single-blinded randomized cross-over design, each after intravenous infusion of either MB (0.5 mg/kg) or placebo. MRI-based measures of Cerebral Blood Flow and Oxygen Extraction Fraction were integrated to compute Cerebral Metabolic Rate of Oxygen in Frontal Lobe, Anterior Cingulate, and Hippocampus-implicated in BD neurometabolic pathophysiology. Inter-daily variation in mood rating was used to assess mood instability. RESULTS: A decrease in global CBF and CMRO2 was observed after acutely administrating MB to all participants. Greater regional CMRO2 reductions were observed after MB, in patients compared to controls in FL (mean = -14.2 ± 19.5 % versus 2.3 ± 14.8 %), ACC (mean = -14.8 ± 23.7 % versus 2.4 ± 15.7 %). The effects on CMRO2 in those regions were primarily driven by patients with longer disease duration and higher mood instability. LIMITATIONS: Sample size; medications potentially impacting on response to MB. CONCLUSIONS: An altered neurometabolic response to MB, a mitochondrial/hemodynamic modulator, was observed in patients, supporting the hypothesis of vulnerability to neurometabolic stress in BD. Integrating quantitative imaging of cerebral oxygen metabolism with a mitochondrial-targeting pharmacological challenge could provide a novel biomarker of neurometabolic and cerebrovascular pathophysiology in BD.

Assessing Leg Blood Flow and Cardiac Output During Running Using Thermodilution.

Cardiac output (Q̇C) and leg blood flow (Q̇LEG) can be measured simultaneously with high accuracy using transpulmonary and femoral vein thermodilution with a single-bolus injection. The invasive measure has offered important insight into leg hemodynamics and blood flow distribution during exercise. Despite being the natural modality of exercise in humans, there has been no direct measure of Q̇LEG while running in humans. We sought to determine the feasibility of the thermodilution technique for measuring Q̇LEG and conductance during high-intensity running, in an exploratory case study. A trained runner (30 years male) completed two maximal incremental tests on a cycle ergometer and motorized treadmill. Q̇LEG and Q̇C were determined using the single-bolus thermodilution technique. Arterial and venous blood were sampled throughout exercise, with continuous monitoring of metabolism, intra-arterial and venous pressure, and temperature. The participant reached a greater peak oxygen uptake (V̇O2peak) during running relative to cycling (74 vs. 68 mL/kg/min) with comparable Q̇LEG (19.0 vs. 19.5 L/min) and Q̇C (27.4 vs. 26.2 L/min). Leg vascular conductance was greater during high-intensity running relative to cycling (82 vs. 70 mL/min/mmHg @ ~80% V̇O2peak). The "beat phenomenon" was apparent in femoral flow while running, producing large gradients in conductance (62-90 mL/min/mmHg @ 70% V̇O2peak). In summary, we present the first direct measure of Q̇LEG and conductance in a running human. Our findings corroborate several assumptions about Q̇LEG during running compared with cycling. Importantly, we demonstrate that using thermodilution in running exercise can be completed effectively and safely.

Cellular and molecular mechanisms of the blood-brain barrier dysfunction in neurodegenerative diseases.

BACKGROUND: Maintaining the structural and functional integrity of the blood-brain barrier (BBB) is vital for neuronal equilibrium and optimal brain function. Disruptions to BBB performance are implicated in the pathology of neurodegenerative diseases. MAIN BODY: Early indicators of multiple neurodegenerative disorders in humans and animal models include impaired BBB stability, regional cerebral blood flow shortfalls, and vascular inflammation associated with BBB dysfunction. Understanding the cellular and molecular mechanisms of BBB dysfunction in brain disorders is crucial for elucidating the sustenance of neural computations under pathological conditions and for developing treatments for these diseases. This paper initially explores the cellular and molecular definition of the BBB, along with the signaling pathways regulating BBB stability, cerebral blood flow, and vascular inflammation. Subsequently, we review current insights into BBB dynamics in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The paper concludes by proposing a unified mechanism whereby BBB dysfunction contributes to neurodegenerative disorders, highlights potential BBB-focused therapeutic strategies and targets, and outlines lessons learned and future research directions. CONCLUSIONS: BBB breakdown significantly impacts the development and progression of neurodegenerative diseases, and unraveling the cellular and molecular mechanisms underlying BBB dysfunction is vital to elucidate how neural computations are sustained under pathological conditions and to devise therapeutic approaches.

Higher cerebral blood flow on four-dimensional flow magnetic resonance imaging in young women.

We investigated the reduction in regional brain volume and cerebral blood flow (CBF) with aging and explored potential sex differences in healthy brains. Three-dimensional (3D) T1-weighted magnetic resonance imaging (MRI), time-of-flight magnetic resonance angiography, and four-dimensional (4D) flow MRI were performed on 129 healthy volunteers aged 22-92 years. The brains of healthy volunteers were segmented into 21 subregions using 3D T1-weighted MRI and CBFs in 16 major intracranial arteries were measured using 4D flow MRI. The cortical gray matter volume decreased linearly with aging, whereas the cerebral white matter volume increased until the 40s and then decreased, and the subcortical gray matter volume changed little with aging. The cortical gray matter volume was significantly associated with the total CBF of the major intracranial arteries distal to the circle of Willis; however, the cerebral white matter and subcortical gray matter volumes were not. Generally, women have higher total CBF than men, particularly in their 40s and younger, despite the smaller intracranial volume and smaller diameters of intracranial arteries than men. This may contribute to the higher incidence of subarachnoid hemorrhage due to cerebral aneurysms and migraine in women.

Cerebral perfusion metrics calculated directly from a hypoxia-induced step change in deoxyhemoglobin.

Resting cerebral perfusion metrics can be calculated from the MRI ΔR2* signal during the first passage of an intravascular bolus of a Gadolinium-based contrast agent (GBCA), or more recently, a transient hypoxia-induced change in the concentration of deoxyhemoglobin ([dOHb]). Conventional analysis follows a proxy process that includes deconvolution of an arterial input function (AIF) in a tracer kinetic model. We hypothesized that the step reduction in magnetic susceptibility accompanying a step decrease in [dOHb] that occurs when a single breath of oxygen terminates a brief episode of lung hypoxia permits direct calculation of relative perfusion metrics. The time course of the ΔR2* signal response enables both the discrimination of blood arrival times and the time course of voxel filling. We calculated the perfusion metrics implied by this step signal change in seven healthy volunteers and compared them to those from conventional analyses of GBCA and dOHb using their AIF and indicator dilution theory. Voxel-wise maps of relative cerebral blood flow and relative cerebral blood volume had a high spatial and magnitude congruence for all three analyses (r > 0.9) and were similar in appearance to published maps. The mean (SD) transit times (s) in grey and white matter respectively for the step response (7.4 (1.1), 8.05 (1.71)) were greater than those for GBCA (2.6 (0.45), 3.54 (0.83)) attributable to the nature of their respective calculation models. In conclusion we believe these calculations of perfusion metrics derived directly from ΔR2* have superior merit to calculations via AIF by virtue of being calculated from a direct signal rather than through a proxy model which encompasses errors inherent in designating an AIF and performing deconvolution calculations.

Prognostic value of angiographic based quantitative flow ratio and anatomic features in intracranial atherosclerotic stenosis.

BACKGROUND: Patients with intracranial atherosclerotic stenosis (ICAS) are prone to stroke recurrence despite aggressive medical treatment. Further assessment of the anatomy and physiology of ICAS is urgently needed to facilitate individualized therapy. We explored the predictive value of angiography based hemodynamic and anatomical features for ICAS patients. METHODS: In this retrospective study, patients with moderate-to-severe stenosis of the middle cerebral artery (MCA) were enrolled. The hemodynamic assessment was performed using the single view Murray's law based quantitative flow ratio (µQFR) approach. The locations of lesions were categorized as perforator rich segments of the MCA (pMCA) and others. Multivariate Cox models were developed to identify significant predictors. The primary outcomes were defined as stroke and transient ischemic attack. RESULTS: Among the 333 patients (median (IQR) age, 56 (49-63) years, 70.3% men) over a median follow-up period of 64.5 months, 50 (15.0%) had the primary outcomes, and 80.0% occurred within 5 years. Patients with lower µQFR values (dichotomized at 0.73) had a higher risk of the 5 year primary outcomes (log rank P=0.023), and good collateral circulation may have attenuated the risk. In the multivariate analyses, µQFR (adjusted HR=0.345; 95% CI 0.155 to 0.766; P=0.009), lesion located in pMCA (adjusted HR=0.377; 95% CI 0.190 to 0.749; P=0.005), and diameter ratio of the internal carotid artery (adjusted HR=4.187; 95% CI 1.071 to 16.370; P=0.040) were significantly associated with the 5 year primary outcomes. CONCLUSIONS: Angiography based µQFR and anatomical features, namely plaque localization and internal carotid artery expansion, could serve as promising prognostic indexes for MCA atherosclerosis.

OCT Angiography of the Retina and the Choroid in the Macula in Patients with Normal Tension Glaucoma and Primary Open Angle Glaucoma.

The aim of this study was to compare vessel density (VD) in the retina and choroid in eyes with primary open angle glaucoma (POAG), normal tension glaucoma (NTG) and controls. Patients with POAG, NTG and controls underwent OCT scanning of the macula and the disc followed by 6 × 6 mm macula OCT angiography (OCTA) imaging. Global and hemifield VD were recorded for the superficial (SVP) and deep (DVP) vascular plexus and the choriocapillaris (CC). The OCT thickness of the nerve fiber layer (NFL) and ganglion cell layer (GCC) was also measured. Data from 65 POAG, 33 NTG and 40 control eyes matched for age were analyzed. Mean SVP VD was lower in NTG and POAG eyes compared to controls (38.8 ± 5.3, 40.7 ± 6.8 and 48.5 ± 4.0%, p < 0.001). Mean DVP VD was lower in NTG and POAG eyes compared to controls (43.1 ± 6.1, 44.5 ± 7.6 and 48.6 ± 5.8%, p = 0.002). There was no difference in SVP VD or DVP VD between the glaucoma groups (p > 0.050). No difference was noted in CC VD between the groups (68.3 ± 2.3, 67.6 ± 3.7 and 68.5 ± 2.6%, p = 0.287). Lower SVP and DVP VD was seen in eyes with glaucoma compared to normal eyes. NTG and POAG eyes had similar VD loss. Eyes with glaucoma manifested similar CC VD compared to controls.

Altered Microvascular Reactivity During a Skin Thermal Challenge Is Associated With Organ Dysfunction and Slow Recovery After Cardiac Surgery.

OBJECTIVES: To assess microvascular reactivity during a skin thermal challenge early post-cardiac surgery and its association with outcomes. DESIGN: Noninvasive physiological study. SETTING: Thirty-five-bed department of intensive care. PARTICIPANTS: Patients admitted to the intensive care unit post-cardiac surgery. INTERVENTIONS: Thermal challenge. MEASUREMENTS AND MAIN RESULTS: A total of 46 patients were included; 14 needed vasoactive or ventilatory support for at least 48 hours (slow recovery), and 32 had a more rapid recovery. Skin blood flow (SBF) was measured on the anterior proximal forearm using skin laser Doppler. A thermal challenge was performed by abruptly increasing local skin temperature from 37°C to 43°C while monitoring SBF. The ratio between SBFs at 43°C and 37°C was calculated to measure microvascular reactivity. SBF at 37°C was not significantly different in patients with a slow recovery and those with a rapid recovery, but SBF after 9 minutes at 43°C was lower (48.5 [17.3-69.0] v 85.1 [45.2-125.7], p < 0.01), resulting in a lower SBF ratio (2.8 [1.5-4.7] v 4.8 [3.7-7.8], p < 0.01). Patients with lower SBF ratios were more likely to have dysfunction of at least one organ (assessed using the sequential organ dysfunction score) 48 hours post-cardiac surgery than those with higher ratios: 88% versus 40% versus 27% (p < 0.01), respectively, for the lowest, middle, and highest tertiles of SBF ratio. In multivariable analysis, a lower SBF ratio was an independent risk factor for slow recovery. CONCLUSIONS: Early alterations in microvascular reactivity, evaluated by a skin thermal challenge, are correlated with organ dysfunction. These observations may help in the development of new, simple, noninvasive monitoring systems in postoperative patients.

Identification of cortical arteries and veins in awake mice using two-photon microscopy.

Distinguishing arteries from veins in the cerebral cortex is critical for studying hemodynamics under pathophysiological conditions, which plays an important role in the diagnosis and treatment of various vessel-related diseases. However, due to the complexity of the cerebral vascular network, it is challenging to identify arteries and veins in vivo. Here, we demonstrate an artery-vein separation method that employs a combination of multiple scanning modes of two-photon microscopy and a custom-designed stereoscopic fixation device for mice. In this process, we propose a novel method for determining the line scanning direction, which allows us to determine the blood flow directions. The vasculature branches have been identified using an optimized z-stack scanning mode, followed by the separation of blood vessel types according to the directions of blood flow and branching patterns. Using this strategy, the penetrating arterioles and penetrating venules in awake mice could be accurately identified and the type of cerebral thrombus has been also successfully isolated without any empirical knowledge or algorithms. Our research presents a new, more accurate, and efficient method for cortical artery-vein separation in awake mice, providing a useful strategy for the application of two-photon microscopy in the study of cerebrovascular pathophysiology.

The effect of post-labeling delay on cerebral blood flow is influenced by age and sex: a study based on arterial spin-labeling magnetic resonance imaging.

Background: Whether the effect of post-labeling delay (PLD) on cerebral blood flow (CBF) is influenced by age and sex in adults is unknown. In this study, we mainly aimed to explore the potential influence of age and sex on the effect of PLD on CBF. Methods: This prospective study enrolled 90 healthy adult volunteers (49.47±15.63 years of age; age range, 20-77 years; 47 female; 43 male). All participants underwent 3-dimensional (3D) pseudo-continuous arterial spin labeling (ASL) imaging with 3 different PLDs (1,525, 2,025, and 2,525 ms). The CBF values for each PLD, the arterial transit time (ATT), and the spatial coefficient of variation (spatial CoV) were computed for 21 regions of interest (ROIs) in every participant. Multivariate regression analysis was conducted to assess the potential influence of age and sex on the effect of PLD on CBF and the relationships among CBF, ATT, PLD, age, sex, and spatial CoV. Results: The CBF increased for 7.32 to 9.87 mL/100 g/min as the PLD increased per 1 second in the global gray matter, bilateral frontal, temporal lobes, the vascular territories of bilateral anterior and middle carotid artery. When the age increased per 1 year, the speed of the changes for CBF decreased for 0.26 to 0.3 mL/100 g/min/s in these regions. However, the CBF decreased for 12 to 17 mL/100 g/min as the PLD increased per 1 second in the bilateral limbic lobes, insula, and deep gray matter. In these regions, the speed of the changes for CBF increased for 0.2 to 0.28 mL/100 g/min/s as the age increased per 1 year. Furthermore, compared to the female, the speed of the changes for CBF decreased for 3.58 to 4.6 mL/100 g/min/s for the male in global gray matter, bilateral frontal, limbic lobes, and the vascular territories of bilateral anterior carotid artery, and the speed increased 4.49 to 5.09 mL/100 g/min/s for the male in the limbic lobes. In addition, the CBF decreased with aging and the CBF tended to be higher in females compared to males. At the same time, we found that the ATT of all ROIs increased with age and manifested higher in males than females. Moreover, we found that CBF decreased with the increase of ATT, and the effect of ATT on CBF was less influenced by PLD. Finally, we found that the spatial CoV of ASL in certain regions increased with the increase of ATT and age, and was greater in males. Conclusions: The effect of PLD on CBF can be influenced by age and sex. The relationships among CBF, ATT, PLD, age, sex, and spatial CoV found in this study may have certain significance for the study of ASL imaging in the future.

Quantitative transport mapping of multi-delay arterial spin labeling MRI detects early blood perfusion alterations in Alzheimer's disease.

BACKGROUND: Quantitative transport mapping (QTM) of blood velocity, based on the transport equation has been demonstrated higher accuracy and sensitivity of perfusion quantification than the traditional Kety's method-based cerebral blood flow (CBF). This study aimed to investigate the associations between QTM velocity and cognitive function in Alzheimer's disease (AD) using multiple post-labeling delay arterial spin labeling (ASL) MRI. METHODS: A total of 128 subjects (21 normal controls (NC), 80 patients with mild cognitive impairment (MCI), and 27 AD) were recruited prospectively. All participants underwent MRI examination and neuropsychological evaluation. QTM velocity and traditional CBF maps were computed from multiple delay ASL. Regional quantitative perfusion measurements were performed and compared to study group differences. We tested the hypothesis that cognition declines with reduced cerebral blood perfusion with consideration of age and gender effects. RESULTS: In cortical gray matter (GM) and the hippocampus, QTM velocity and CBF showed decreased values in the AD group compared to NC and MCI groups; QTM velocity, but not CBF, showed a significant difference between MCI and NC groups. QTM velocity and CBF showed values decreasing with age; QTM velocity, but not CBF, showed a significant gender difference between male and female. QTM velocity and CBF in the hippocampus were positively correlated with cognition, including global cognition, memory, executive function, and language function. CONCLUSION: This study demonstrated an increased sensitivity of QTM velocity as compared with the traditional Kety's method-based CBF. Specifically, we observed only in QTM velocity, reduced perfusion velocity in GM and the hippocampus in MCI compared with NC. Both QTM velocity and CBF demonstrated a reduction in AD vs. controls. Decreased QTM velocity and CBF in the hippocampus were correlated with poor cognitive measures. These findings suggest QTM velocity as potential biomarker for early AD blood perfusion alterations and it could provide an avenue for early intervention of AD.

Cerebral blood flow in relation to peripheral endothelial function in youth bipolar disorder.

INTRODUCTION: Anomalous cerebral blood flow (CBF) is evident in bipolar disorder (BD), however the extent to which CBF reflects peripheral vascular function in BD is unknown. This study investigated endothelial function, an index of early atherosclerosis and cardiovascular disease risk, in relation to CBF among youth with BD. METHODS: Participants included 113 youth, 13-20 years old (66 BD; 47 healthy controls [HC]). CBF was measured using arterial spin labeling with 3T MRI. Region of interest analyses (ROI; global grey matter, middle frontal gyrus, anterior cingulate cortex, temporal cortex, caudate) were undertaken alongside voxel-wise analyses. Reactive hyperemia index (RHI), a measure of endothelial function, was assessed non-invasively via pulse amplitude tonometry. General linear models were used to examine RHI and RHI-by-diagnosis associations with CBF, controlling for age, sex, and body mass index. Bonferroni correction for multiple comparisons was used for ROI analyses, such that the significance level was divided by the number of ROIs (α = 0.05/5 = 0.01). Cluster-extent thresholding was used to correct for multiple comparisons for voxel-wise analyses. RESULTS: ROI findings were not significant after correction. Voxel-wise analyses found that higher RHI was associated with lower left thalamus CBF in the whole group (p < 0.001). Additionally, significant RHI-by-diagnosis associations with CBF were found in three clusters: left intracalcarine cortex (p < 0.001), left thalamus (p < 0.001), and right frontal pole (p = 0.006). Post-hoc analyses showed that in each cluster, higher RHI was associated with lower CBF in BD, but higher CBF in HC. CONCLUSION: We found that RHI was differentially associated with CBF in youth with BD versus HC. The unanticipated association of higher RHI with lower CBF in BD could potentially reflect a compensatory mechanism. Future research, including prospective studies and experimental designs are warranted to build on the current findings.

Ultrasound Speckle Decorrelation Analysis-Based Velocimetry for 3D-Velocity-Components Measurement Using a 1D Transducer Array.

Ultrasound velocimetry has been widely used for blood flow imaging. However, the flow measurements are constrained to resolve the in-plane 2D flow components when using a 1D transducer array. In this work, an ultrasound speckle decorrelation analysis-based velocimetry (3C-vUS) is proposed for 3D velocity components measurement using a 1D transducer array. The 3C-vUS theory is first derived and validated with numerical simulations and phantom experiments. The in vivo testing results show that 3C-vUS can accurately measure the blood flow 3D-velocity-components of the human carotid artery at arbitrary probe-to-vessel angles throughout the cardiac cycle. With such capability, the 3C-vUS will alleviate the requirement of operators and promote disease screening for blood flow-related disorders.

Engaging Mood Brain Circuits with Psilocybin (EMBRACE): a study protocol for a randomized, placebo-controlled and delayed-start, neuroimaging trial in depression.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide across domains of health and cognition, affecting overall quality of life. Approximately one third of individuals with depression do not fully respond to treatments (e.g., conventional antidepressants, psychotherapy) and alternative strategies are needed. Recent early phase trials suggest psilocybin may be a safe and efficacious intervention with rapid-acting antidepressant properties. Psilocybin is thought to exert therapeutic benefits by altering brain network connectivity and inducing neuroplastic changes that endure for weeks post-treatment. Although early clinical results are encouraging, psilocybin's acute neurobiological effects on neuroplasticity have not been fully investigated. We aim to examine for the first time how psilocybin acutely (intraday) and subacutely (weeks) alters functional brain networks implicated in depression. METHODS: Fifty participants diagnosed with MDD or persistent depressive disorder (PDD) will be recruited from a tertiary mood disorders clinic and undergo 1:1 randomization into either an experimental or control arm. Participants will be given either 25 mg psilocybin or 25 mg microcrystalline cellulose (MCC) placebo for the first treatment. Three weeks later, those in the control arm will transition to receiving 25 mg psilocybin. We will investigate whether treatments are associated with changes in arterial spin labelling and blood oxygenation level-dependent contrast neuroimaging assessments at acute and subacute timepoints. Primary outcomes include testing whether psilocybin demonstrates acute changes in (1) cerebral blood flow and (2) functional brain activity in networks associated with mood regulation and depression when compared to placebo, along with changes in MADRS score over time compared to placebo. Secondary outcomes include changes across complementary clinical psychiatric, cognitive, and functional scales from baseline to final follow-up. Serum peripheral neurotrophic and inflammatory biomarkers will be collected at baseline and follow-up to examine relationships with clinical response, and neuroimaging measures. DISCUSSION: This study will investigate the acute and additive subacute neuroplastic effects of psilocybin on brain networks affected by depression using advanced serial neuroimaging methods. Results will improve our understanding of psilocybin's antidepressant mechanisms versus placebo response and whether biological measures of brain function can provide early predictors of treatment response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06072898. Registered on 6 October 2023.

Neurovascular coupling dysfunction associated with cognitive impairment in presbycusis.

The neuropathological mechanism underlying presbycusis remains unclear. This study aimed to illustrate the mechanism of neurovascular coupling associated with cognitive impairment in patients with presbycusis. We assessed the coupling of cerebral blood perfusion with spontaneous neuronal activity by calculating the correlation coefficients between cerebral blood flow and blood oxygen level-dependent-derived quantitative maps (amplitude of low-frequency fluctuation, fractional amplitude of low-frequency fluctuation, regional homogeneity, degree centrality). Four neurovascular coupling metrics (cerebral blood flow-amplitude of low-frequency fluctuation, cerebral blood flow-fractional amplitude of low-frequency fluctuation, cerebral blood flow-regional homogeneity and cerebral blood flow-degree centrality) were compared at the global and regional levels between the presbycusis group and the healthy control group, and the intrinsic association between the altered neurovascular coupling metrics and the neuropsychological scale was further analysed in the presbycusis group. At the global level, neurovascular coupling was significantly lower in the presbycusis group than in the control group and partially related to cognitive level. At the regional level, neurovascular biomarkers were significantly elevated in three brain regions and significantly decreased in one brain region, all of which involved the Papez circuit. Regional neurovascular coupling provides more information than global neurovascular coupling, and neurovascular coupling dysfunction within the Papez circuit has been shown to reveal the causes of poor cognitive and emotional responses in age-related hearing loss patients.

Blunted brachial blood flow velocity response to acute mental stress in PTSD females.

Post-traumatic stress disorder (PTSD) is associated with increased cardiovascular disease (CVD) risk. Compared with males, females are twice as likely to develop PTSD after trauma exposure, and cardiovascular reactivity to stress is a known risk factor for CVD. We aimed to examine hemodynamic responses to acute mental stress in trauma-exposed females with and without a clinical diagnosis of PTSD. We hypothesized that females with PTSD would have higher heart rate (HR), blood pressure (BP), and lower blood flow velocity (BFV) responsiveness compared with controls. We enrolled 21 females with PTSD and 21 trauma-exposed controls. We continuously measured HR using a three-lead electrocardiogram, BP using finger plethysmography, and brachial BFV using Doppler ultrasound. All variables were recorded during 10 min of supine rest, 5 min of mental arithmetic, and 5 min of recovery. Females with PTSD were older, and had higher BMI and higher resting diastolic BP. Accordingly, age, BMI, and diastolic BP were covariates for all repeated measures analyses. Females with PTSD had a blunted brachial BFV response to mental stress (time × group, p = 0.005) compared with controls, suggesting greater vasoconstriction. HR and BP responses were comparable. In conclusion, our results suggest early impairment of vascular function in premenopausal females with PTSD.

Multimodality assessment of the coronary microvasculature with TIMI frame count versus perfusion PET highlights coronary changes characteristic of coronary microvascular disease.

Background: The diagnosis of coronary microvascular disease (CMVD) remains challenging. Perfusion PET-derived myocardial blood flow (MBF) reserve (MBFR) can quantify CMVD but is not widely available. Thrombolysis in Myocardial Infarction (TIMI) frame count (TFC) is an angiography-based method that has been proposed as a measure of CMVD. Here, we compare TFC and PET-derived MBF measurements to establish the role of TFC in assessing for CMVD. We use coronary modeling to elucidate the relationship between MBFR and TFC and propose TFC thresholds for identifying CMVD. Methods: In a cohort of 123 individuals (age 58 ± 12.1, 63% women, 41% Caucasian) without obstructive coronary artery disease who had undergone perfusion PET and coronary angiography for clinical indications, we compared TFC and perfusion PET parameters using Pearson correlation (PCC) and linear regression modeling. We used mathematical modeling of the coronary circulation to understand the relationship between these parameters and performed Receiver Operating Curve (ROC) analysis. Results: We found a significant negative correlation between TFC and MBFR. Sex, race and ethnicity, and nitroglycerin administration impact this relationship. Coronary modeling showed an uncoupling between TFC and flow in epicardial vessels. In ROC analysis, TFC performed well in women (AUC 0.84-0.89) and a moderately in men (AUC 0.68-0.78). Conclusions: We established an inverse relationship between TFC and PET-derived MBFR, which is affected by patient selection and procedural factors. TFC represents a measure of the volume of the epicardial coronary compartment, which is increased in patients with CMVD, and performs well in identifying women with CMVD.