Brain perfusion estimation by Tikhonov model-free deconvolution in a long axial field of view PET/CT scanner exploring five different PET tracers.

PURPOSE: New total-body PET scanners with a long axial field of view (LAFOV) allow for higher temporal resolution due to higher sensitivity, which facilitates perfusion estimation by model-free deconvolution. Fundamental tracer kinetic theory predicts that perfusion can be estimated for all tracers despite their different fates given sufficiently high temporal resolution of 1 s or better, bypassing the need for compartment modelling. The aim of this study was to investigate whether brain perfusion could be estimated using model-free Tikhonov generalized deconvolution for five different PET tracers, [15O]H2O, [11C]PIB, [18F]FE-PE2I, [18F]FDG and [18F]FET. To our knowledge, this is the first example of a general model-free approach to estimate cerebral blood flow (CBF) from PET data. METHODS: Twenty-five patients underwent dynamic LAFOV PET scanning (Siemens, Quadra). PET images were reconstructed with an isotropic voxel resolution of 1.65 mm3. Time framing was 40 × 1 s during bolus passage followed by increasing framing up to 60 min. AIF was obtained from the descending aorta. Both voxel- and region-based calculations of perfusion in the thalamus were performed using the Tikhonov method. The residue impulse response function was used to estimate the extraction fraction of tracer leakage across the blood-brain barrier. RESULTS: CBF ranged from 37 to 69 mL blood min-1 100 mL of tissue-1 in the thalamus. Voxelwise calculation of CBF resulted in CBF maps in the physiologically normal range. The extraction fractions of [15O]H2O, [18F]FE-PE2I, [11C]PIB, [18F]FDG and [18F]FET in the thalamus were 0.95, 0.78, 0.62, 0.19 and 0.03, respectively. CONCLUSION: The high temporal resolution and sensitivity associated with LAFOV PET scanners allow for noninvasive perfusion estimation of multiple tracers. The method provides an estimation of the residue impulse response function, from which the fate of the tracer can be studied, including the extraction fraction, influx constant, volume of distribution and transit time distribution, providing detailed physiological insight into normal and pathologic tissue.

Reproducibility of cerebral blood flow, oxygen metabolism, and lactate and N-acetyl-aspartate concentrations measured using magnetic resonance imaging and spectroscopy.

In humans, resting cerebral perfusion, oxygen consumption and energy metabolism demonstrate large intersubject variation regardless of methodology. Whether a similar large variation is also present longitudinally in individual subjects is much less studied, but knowing the time variance in reproducibility is important when designing and interpreting longitudinal follow-up studies examining brain physiology. Therefore, we examined the reproducibility of cerebral blood flow (CBF), global cerebral metabolic rate of oxygen (CMRO2), global arteriovenous oxygen saturation difference (A-V.O2), and cerebral lactate and N-acetyl-aspartate (NAA) concentrations measured using magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques through repeated measurements at 6 h, 24 h, 7 days and several weeks after initial baseline measurements in young healthy adults (N = 26, 13 females, age range 18-35 years). Using this setup, we calculated the correlation, limit of agreement (LoA) and within-subject coefficient of variation (CoVWS) between baseline values and the subsequent repeated measurements to examine the longitudinal variation in individual cerebral physiology. CBF and CMRO2 correlated significantly between baseline and all subsequent measurements. The strength of the correlations (R2) and reproducibility metrics (LoA and CoVWS) demonstrated the best reproducibility for the within-day measurements and generally declined with longer time between measurements. Cerebral lactate and NAA concentrations also correlated significantly for all measurements, except between baseline and the 7-day measurement for lactate. Similar to CBF and CMRO2, lactate and NAA demonstrated the best reproducibility for within-day repeated measurements. The gradual decline in reproducibility over time should be considered when designing and interpreting studies on brain physiology, for example, in the evaluation of treatment efficacy.

Evaluation of the effects of ezetimibe on albuminuria and kidney fat in individuals with type 2 diabetes and chronic kidney disease.

AIM: To investigate the effects of ezetimibe on the urine albumin creatinine ratio (UACR) and kidney parenchyma fat content (kidney-PF) in individuals with type 2 diabetes (T2D) and early chronic kidney disease. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled study of ezetimibe 10 mg once daily for 16 weeks in individuals with T2D and a UACR of 30 mg/g or higher was conducted. Kidney-PF was assessed with magnetic resonance spectroscopy. Geometric mean changes from baseline were derived from linear regressions. RESULTS: A total of 49 participants were randomized to ezetimibe (n = 25) or placebo (n = 24). Overall, mean ± standard deviation age was 67 ± 7 years, body mass index was 31 ± 4 kg/m2 and the proportion of men was 84%. The mean estimated glomerular filtration rate was 76 ± 22 mL/min/1.73m2 and median (first-third quartile) UACR was 95 (41-297) mg/g. Median kidney-PF was 1.0% (0.3%-2.1%). Compared with placebo, ezetimibe did not significantly reduce UACR (mean [95% confidence interval] change: -3% [-28%-31%]) or kidney-PF (mean change: -38% [-66%-14%]). In participants with baseline kidney-PF above the median, ezetimibe reduced kidney-PF significantly (mean change: -60% [-84%--3%]) compared with placebo, while the reduction in UACR was not significant (mean change: -28% [-54%-15%]). CONCLUSIONS: Ezetimibe did not reduce the UACR or kidney-PF on top of modern T2D management. However, kidney-PF was reduced with ezetimibe in participants with high baseline kidney-PF.

Scanner agnostic large-scale evaluation of MS lesion delineation tool for clinical MRI.

Introduction: Patients with MS are MRI scanned continuously throughout their disease course resulting in a large manual workload for radiologists which includes lesion detection and size estimation. Though many models for automatic lesion segmentation have been published, few are used broadly in clinic today, as there is a lack of testing on clinical datasets. By collecting a large, heterogeneous training dataset directly from our MS clinic we aim to present a model which is robust to different scanner protocols and artefacts and which only uses MRI modalities present in routine clinical examinations. Methods: We retrospectively included 746 patients from routine examinations at our MS clinic. The inclusion criteria included acquisition at one of seven different scanners and an MRI protocol including 2D or 3D T2-w FLAIR, T2-w and T1-w images. Reference lesion masks on the training (n = 571) and validation (n = 70) datasets were generated using a preliminary segmentation model and subsequent manual correction. The test dataset (n = 100) was manually delineated. Our segmentation model https://github.com/CAAI/AIMS/ was based on the popular nnU-Net, which has won several biomedical segmentation challenges. We tested our model against the published segmentation models HD-MS-Lesions, which is also based on nnU-Net, trained with a more homogenous patient cohort. We furthermore tested model robustness to data from unseen scanners by performing a leave-one-scanner-out experiment. Results: We found that our model was able to segment MS white matter lesions with a performance comparable to literature: DSC = 0.68, precision = 0.90, recall = 0.70, f1 = 0.78. Furthermore, the model outperformed HD-MS-Lesions in all metrics except precision = 0.96. In the leave-one-scanner-out experiment there was no significant change in performance (p < 0.05) between any of the models which were only trained on part of the dataset and the full segmentation model. Conclusion: In conclusion we have seen, that by including a large, heterogeneous dataset emulating clinical reality, we have trained a segmentation model which maintains a high segmentation performance while being robust to data from unseen scanners. This broadens the applicability of the model in clinic and paves the way for clinical implementation.

Multimodality Imaging in Cranial Giant Cell Arteritis: First Experience with High-Resolution T1-Weighted 3D Black Blood without Contrast Enhancement Magnetic Resonance Imaging.

In order to support or refute the clinical suspicion of cranial giant cell arteritis (GCA), a supplemental imaging modality is often required. High-resolution black blood Magnetic Resonance Imaging (BB MRI) techniques with contrast enhancement can visualize artery wall inflammation in GCA. We compared findings on BB MRI without contrast enhancement with findings on 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/low-dose computed tomography (2-[18F]FDG PET/CT) in ten patients suspected of having GCA and in five control subjects who had a 2-[18F]FDG PET/CT performed as a routine control for malignant melanoma. BB MRI was consistent with 2-[18F]FDG PET/CT in 10 out of 10 cases in the group with suspected GCA. In four out of five cases in the control group, the BB MRI was consistent with 2-[18F]FDG PET/CT. In this small population, BB MRI without contrast enhancement shows promising performance in the diagnosis of GCA, and might be an applicable imaging modality in patients.

Subclinical cognitive deficits are associated with reduced cerebrovascular response to visual stimulation in mid-sixties men.

Reduced cerebrovascular response to neuronal activation is observed in patients with neurodegenerative disease. In the present study, we examined the correlation between reduced cerebrovascular response to visual activation (ΔCBFVis.Act) and subclinical cognitive deficits in a human population of mid-sixties individuals without neurodegenerative disease. Such a correlation would suggest that impaired cerebrovascular function occurs before overt neurodegenerative disease. A total of 187 subjects (age 64-67 years) of the Metropolit Danish Male Birth Cohort participated in the study. ΔCBFVis.Act was measured using arterial spin labelling (ASL) MRI. ΔCBFVis.Act correlated positively with cognitive performance in: Global cognition (p = 0.046), paired associative memory (p = 0.025), spatial recognition (p = 0.026), planning (p = 0.016), simple processing speed (p < 0.01), and with highly significant correlations with current intelligence (p < 10-5), and more complex processing speed (p < 10-3), the latter two explaining approximately 11-13% of the variance. Reduced ΔCBFVis.Act was independent of brain atrophy. Our findings suggest that inhibited cerebrovascular response to neuronal activation is an early deficit in the ageing brain and associated with subclinical cognitive deficits. Cerebrovascular dysfunction could be an early sign of a trajectory pointing towards the development of neurodegenerative disease. Future efforts should elucidate if maintenance of a healthy cerebrovascular function can protect against the development of dementia.

Blood-brain barrier permeability changes in the first year after alemtuzumab treatment predict 2-year outcomes in relapsing-remitting multiple sclerosis.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), early disease control reduces the risk of permanent disability. The blood-brain barrier (BBB) is compromised in MS, and its permeability is a potential biomarker. OBJECTIVE: To investigate BBB permeability measured by MRI as a marker of alemtuzumab efficacy. METHODS: Patients with RRMS initiating alemtuzumab treatment were recruited prospectively. BBB permeability was assessed as the Patlak-derived influx constant (Ki) by dynamic contrast-enhanced MRI before and 6, 12, and 18 months after the first course of alemtuzumab. No Evidence of Disease Activity-3 (NEDA-3) status was ascertained two years after treatment initiation. RESULTS: Patients who maintained NEDA-3 status at two years (n = 7) had a larger decrease in Ki between baseline and six months (-0.029 ml/100 g/min [CI -0.005 - -0.053]) and between baseline and 12 months in normal appearing white matter (0.043 [CI 0.022 - -0.065]), than those who experienced disease activity (n = 8). ROC curve analysis of the Ki change between baseline and 12 months in NAWM predicted a loss of NEDA status at 2 years with 86% sensitivity and 86% specificity (AUC 0.98, p = 0.002). CONCLUSION: BBB permeability predicted alemtuzumab efficacy at two years, indicating that BBB permeability is a biomarker of treatment response in RRMS.

Kidney oxygenation, perfusion and blood flow in people with and without type 1 diabetes.

Background: We used magnetic resonance imaging (MRI) to study kidney energetics in persons with and without type 1 diabetes (T1D). Methods: In a cross-sectional study, 15 persons with T1D and albuminuria and 15 non-diabetic controls (CONs) underwent multiparametric MRI (3 Tesla Philips Scanner) to quantify renal cortical and medullary oxygenation (R2*, higher values correspond to higher deoxyhaemoglobin concentration), renal perfusion (arterial spin labelling) and renal artery blood flow (phase contrast). Analyses were adjusted for age, sex, systolic blood pressure, plasma haemoglobin, body mass index and estimated glomerular filtration rate (eGFR). Results: Participants with T1D had a higher median (Q1; Q3) urine albumin creatinine ratio (UACR) than CONs [46 (21; 58) versus 4 (3; 6) mg/g; P < .0001] and a lower mean ± SD eGFR (73 ± 32 mL/min/1.73 m2 versus 88 ± 15 mL/min/1.73 m2;  P = .12), although not significantly. Mean medullary R2* was lower in T1D (34 ± 6/s versus 38 ± 5/s; P < .01) corresponding to a higher oxygenation. R2* was not different in the cortex. Cortical perfusion was lower in T1D (163 ± 40 versus 224 ± 49 mL/100 g/min; P < .001). Renal artery blood flow was lower in T1D than in CONs (360 ± 130 versus 430 ± 113 mL/min; P = .05). In T1D, lower cortical oxygenation and renal artery blood flow were both associated with higher UACR and lower eGFR (P < .05). Conclusions: Participants with T1D and albuminuria exhibited higher medullary oxygenation than CONs, despite lower cortical perfusion and renal artery blood flow. This might reflect perturbed kidney energetics leading to a higher setpoint of medullary oxygenation in T1D. Lower cortical oxygenation and renal artery blood flow were associated with higher UACR and lower eGFR in T1D.

Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial.

BACKGROUND: Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) slow the progression of diabetic kidney disease, possibly by reducing the proximal tubule transport workload with subsequent improvement of renal oxygenation. We aimed to test this hypothesis in individuals with type 1 diabetes and albuminuria. METHODS: A randomised, double-blind, placebo-controlled, crossover trial with a single 50 mg dose of the SGLT2 inhibitor dapagliflozin and placebo in random order, separated by a two-week washout period. Magnetic resonance imaging (MRI) was used to assess renal R2* (a low value corresponds to a high tissue oxygenation), renal perfusion (arterial spin labelling) and renal artery flow (phase contrast imaging) at baseline, three- and six hours from tablet ingestion. Exploratory outcomes, including baroreflex sensitivity, peripheral blood oxygen saturation, peripheral blood mononuclear cell mitochondrial oxygen consumption rate, and biomarkers of inflammation were evaluated at baseline and 12 h from medication. The study is registered in the EU Clinical Trials Register (EudraCT 2019-004,557-92), on ClinicalTrials.gov (NCT04193566), and is completed. FINDINGS: Between February 3, 2020 and October 23, 2020, 31 individuals were screened, and 19 eligible individuals were randomised. Three dropped out before receiving any of the interventions and one dropped out after receiving only placebo. We included 15 individuals (33% female) in the per-protocol analysis with a mean age of 58 (SD 14) years, median urinary albumin creatinine ratio of 46 [IQR 21-58] mg/g and an eGFR of 73 (32) ml/min/1·73m2. The mean changes in renal cortical R2* from baseline to six hours were for dapagliflozin -1·1 (SD 0·7) s-1 and for placebo +1·3 (0·7) s-1, resulting in a difference between interventions of -2·3 s-1 [95% CI -4·0 to -0·6]; p = 0·012. No between-intervention differences were found in any other MRI outcomes, physiological parameters or exploratory outcomes. There were no adverse events. INTERPRETATION: A single dose of 50 mg dapagliflozin acutely improved renal cortical R2* without changing renal perfusion or blood flow. This suggests improved renal cortical oxygenation due to a reduced tubular transport workload in the proximal tubules. Such improved oxygenation may in part explain the long-term beneficial renal effects seen with SGLT2 inhibitors, but it remains to be determined whether the observed effects can be achieved with lower doses, with chronic treatment and if they occur in type 2 diabetes as well.

Associations Between Cognitive Function and Levels of Glutamatergic Metabolites and Gamma-Aminobutyric Acid in Antipsychotic-Naïve Patients With Schizophrenia or Psychosis.

BACKGROUND: Abnormal glutamate and GABA (gamma-aminobutyric acid) levels have been found in the early phase of schizophrenia and may underlie cognitive deficits. However, the association between cognitive function and levels of glutamatergic metabolites and GABA has not been investigated in a large group of antipsychotic-naïve patients. METHODS: In total, 56 antipsychotic-naïve patients with schizophrenia or psychotic disorder and 51 healthy control subjects underwent magnetic resonance spectroscopy to measure glutamate, glutamate+glutamine (Glx), and GABA levels in dorsal anterior cingulate cortex (ACC) and glutamate and Glx levels in left thalamus. The cognitive domains of attention, working memory, and IQ were assessed. RESULTS: The whole group of antipsychotic-naïve patients had lower levels of GABA in dorsal ACC (p = .03), and the subgroup of patients with a schizophrenia diagnosis had higher glutamate levels in thalamus (p = .01), but Glx levels in dorsal ACC and thalamus did not differ between groups. Glx levels in dorsal ACC were positively associated with working memory (logarithmically transformed: b = -.016 [higher score indicates worse performance], p = .005) and attention (b = .056, p = .035) in both patients and healthy control subjects, although the association with attention did not survive adjustment for multiple comparisons. CONCLUSIONS: The findings suggest a positive association between glutamatergic metabolites and cognitive function that do not differ between patients and healthy control subjects. Moreover, our data indicate that decreased GABAergic levels in dorsal ACC are involved in schizophrenia and psychotic disorder, whereas increased glutamate levels in thalamus seem to be implicated in schizophrenia pathophysiology. The findings imply that first-episode patients with cognitive deficits may gain from glutamate-modulating compounds.

Volume of hippocampal subregions and clinical improvement following electroconvulsive therapy in patients with depression.

It is thought that the hippocampal neurogenesis is an important mediator of the antidepressant effect of electroconvulsive therapy (ECT). However, most previous studies failed to demonstrate the relationship between the increase in the hippocampal volume and the antidepressant effect. We reinvestigated this relationship by looking at distinct hippocampal subregions and applying repeated measures correlation. Using a 3 Tesla MRI-scanner, we scanned 22 severely depressed in-patients at three time points: before the ECT series, after the series, and at six-month follow-up. The depression severity was assessed by the 17-item Hamilton Rating Scale for Depression (HAMD-17). The hippocampus was segmented into subregions using Freesurfer software. The dentate gyrus (DG) was the primary region of interest (ROI), due to the role of this region in neurogenesis. The other major hippocampal subregions were the secondary ROIs (n = 20). The general linear mixed model and the repeated measures correlation were used for statistical analyses. Immediately after the ECT series, a significant volume increase was present in the right DG (Cohen's d = 1.7) and the left DG (Cohen's d = 1.5), as well as 15 out of 20 secondary ROIs. The clinical improvement, i.e., the decrease in HAMD-17 score, was correlated to the increase in the right DG volume (rrm = -0.77, df = 20, p < .001), and the left DG volume (rrm = -0.75, df = 20, p < .001). Similar correlations were observed in 14 out of 20 secondary ROIs. Thus, ECT induces an increase not only in the volume of the DG, but also in the volume of other major hippocampal subregions. The volumetric increases may reflect a neurobiological process that may be related to the ECT's antidepressant effect. Further investigation of the relationship between hippocampal subregions and the antidepressant effect is warranted. A statistical approach taking the repeated measurements into account should be preferred in the analyses.

Neuroplasticity induced by general anaesthesia: study protocol for a randomised cross-over clinical trial exploring the effects of sevoflurane and propofol on the brain - A 3-T magnetic resonance imaging study of healthy volunteers.

BACKGROUND: Although used extensively worldwide, the effects of general anaesthesia on the human brain remain largely elusive. Moreover, general anaesthesia may contribute to serious conditions or adverse events such as postoperative cognitive dysfunction and delirium. To understand the basic mechanisms of general anaesthesia, this project aims to study and compare possible de novo neuroplastic changes induced by two commonly used types of general anaesthesia, i.e. inhalation anaesthesia by sevoflurane and intravenously administered anaesthesia by propofol. In addition, we wish to to explore possible associations between neuroplastic changes, neuropsychological adverse effects and subjective changes in fatigue and well-being. METHODS: This is a randomised, participant- and assessor-blinded, cross-over clinical trial. Thirty healthy volunteers (male:female ratio 1:1) will be randomised to general anaesthesia by either sevoflurane or propofol. Multimodal magnetic resonance imaging (MRI) of the brain will be performed before and after general anaesthesia and repeated after 1 and 8 days. Each magnetic resonance imaging session will be accompanied by cognitive testing and questionnaires on fatigue and well-being. After a wash-out period of 4 weeks, the volunteers will receive the other type of anaesthetic (sevoflurane or propofol), followed by the same series of tests. Primary outcomes: changes in T1-weighted 3D anatomy and diffusion tensor imaging. SECONDARY OUTCOMES: changes in resting-state functional magnetic resonance imaging, fatigue, well-being, cognitive function, correlations between magnetic resonance imaging findings and the clinical outcomes (questionnaires and cognitive function). Exploratory outcomes: changes in cerebral perfusion and oxygen metabolism, lactate, and response to visual stimuli. DISCUSSION: To the best of our knowledge, this is the most extensive and advanced series of studies with head-to-head comparison of two widely used methods for general anaesthesia. Recruitment was initiated in September 2019. TRIAL REGISTRATION: Approved by the Research Ethics Committee in the Capital Region of Denmark, ref. H-18028925 (6 September 2018). EudraCT and Danish Medicines Agency: 2018-001252-35 (23 March 2018). www.clinicaltrials.gov , ID: NCT04125121 . Retrospectively registered on 10 October 2019.

Volume of the rectus capitis posterior minor muscle in migraine patients: a cross-sectional structural MRI study.

BACKGROUND: Neck pain in migraine patients is very prevalent between and during migraine attacks, but the underlying mechanism behind neck pain in migraine is unknown. The neck muscle rectus capitis posterior minor muscle (RCPmi) may be important since it is connected to the occipital dura mater. In this study, we examined the RCPmi volume in migraine patients and compared with controls. METHODS: We conducted a cross-sectional MRI study examining muscle volume in 40 episodic migraine patients and 40 controls in preexisting images from prior studies. Three-dimensional T1 weighted sequences were collected with a 3.0 T MRI Scanner. The volume of RCPmi was examined by manually tracing the muscle circumference with Horos medical image viewer. The observer was blinded to participant information. No information regarding neck pain status during or between migraine attacks were available. RESULTS: The mean RCPmi volume was 1.22cm3 in migraine patients and 1.17cm3 in controls (p = 0.549). We found no differences in RCPmi volume on the pain side vs. the non-pain side (p = 0.237) in patients with unilateral migraine. There were no association between the muscle volume and years with migraine, headache or migraine frequency, age or BMI. CONCLUSIONS: We found no difference in RCPmi volume between migraine patients and controls, suggesting no structural RCPmi pathology in migraine.

Investigation of sumatriptan and ketorolac trometamol in the human experimental model of headache.

BACKGROUND: Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces headache in healthy volunteers but the precise mechanisms by which PACAP38 leads to headache are unclear. We investigated the headache preventive effect of sumatriptan and ketorolac on PACAP38-induced headache in healthy volunteers. In addition, we explored contribution of vascular mechanisms to PACAP38-induced headache using high resolution magnetic resonance angiography. METHODS: Thirty-four healthy volunteers were divided in two groups (A and B) and received infusion of PACAP38 (10 picomol/kg/min) over 20 min. Group A was pretreated with intravenous sumatriptan (4 mg) or ketorolac (30 mg) 20 min before infusion of PACAP38. Group B received infusion of sumatriptan or ketorolac as post-treatment 90 min after infusion of PACAP38. In both experiments, we used a randomized, double-blind, cross-over design. We recorded headache characteristics and circumference of extra-intracerebral arteries. RESULTS: We found no difference in AUC (0-6 h) of PACAP38-induced headache in group A, pretreated with sumatriptan or ketorolac (p = 0.297). There was no difference between sumatriptan and ketorolac in PACAP38-induced circumference change (AUCBaseline-110 min) of MMA (p = 0.227), STA (p = 0.795) and MCA (p = 0.356). In group B, post-treatment with ketorolac reduced PACAP38-headache compared to sumatriptan (p < 0.001). Post-treatment with sumatriptan significantly reduced the circumference of STA (p = 0.039) and MMA (p = 0.015) but not of MCA (p = 0.981) compared to ketorolac. In an explorative analysis, we found that pre-treatment with sumatriptan reduced PACAP38-induced headache compared to no treatment (AUC0-90min). CONCLUSIONS: Post-treatment with ketorolac was more effective in attenuating PACAP38-induced headache compared to sumatriptan. Ketorolac exerted its effect without affecting PACAP38-induced arterial dilation, whereas sumatriptan post-treatment attenuated PACAP38-induced dilation of MMA and STA. Pre-treatment with sumatriptan attenuated PACAP38-induced headache without affecting PACAP38-induced arterial dilation. Our findings suggest that ketorolac and sumatriptan attenuated PACAP38-induced headache in healthy volunteers without vascular effects. TRIAL REGISTRATION: Clinicaltrials.gov (NCT03585894). Registered 13 July 2018.

Effect of pituitary adenylate cyclase-activating polypeptide-27 on cerebral hemodynamics in healthy volunteers: A 3T MRI study.

Pituitary adenylate cyclase-activating polypeptide (PACAP) has emerged as an important signaling peptide in migraine pathogenesis. Recently, we have shown that the less-abundant PACAP isoform, PACAP27, induced migraine and headache in patients equipotently to PACAP38. The present study examined the effect of PACAP27 on cerebral hemodynamics in healthy volunteers using high resolution magnetic resonance angiography (MRA). Eighteen healthy volunteers received infusion of PACAP27 (10 pmol/kg/min) or placebo over 20 min and were scanned repeatedly in fixed intervals for 5 h in a double-blind, randomized, placebo-controlled study. The circumference of extra-intracerebral arteries was measured and compared with PACAP38 data. We found significant dilation of middle meningeal artery (MMA) (p = 0.019), superficial temporal artery (p = 0.001) and external carotid artery (p = 0.039) after PACAP27 infusion compared to placebo. Whereas the middle cerebral artery (MCA) (p = 0.011) and internal carotid artery (ICA) (pICAcervical = 0.015, pICAcerebral = 0.019) were constricted. No effects on basilar artery (p = 0.708) and cavernous portion of ICA were found. Post hoc analyses revealed significant larger area under the curve for MMA after PACAP38 compared to PACAP27 (p = 0.033). We also found that PACAP27 induced headache in nine out of twelve (75%) volunteers and one (17%) after placebo. In conclusion, PACAP27 induced headache and dilated extracerebral arteries (>5 h) and slightly constricted MCA in healthy volunteers. Post hoc analysis of PACAP38 data compared with PACAP27 showed that PACAP isoforms dilates MMA with significantly different magnitude.

Ultra-high field MR angiography in human migraine models: a 3.0 T/7.0 T comparison study.

BACKGROUND: Sildenafil and calcitonin gene-related peptide both dilate the intradural segments of the middle meningeal artery measured with 3.0 tesla (T) MR angiography. Here we hypothesized that an increase in field strength to 7.0 T and concomitant enhanced voxel resolution would lower variance in measurements of dilation in the intradural middle meningeal artery. METHODS: Five subjects completed two sessions at respectively 3.0 T and 7.0 T. Each session comprised MR angiography scans once before and twice after administration of sildenafil, calcitonin gene-related peptide or placebo in a three-way, crossover, double-blind, placebo-controlled design. RESULTS: Standard deviations of arterial circumference revealed no difference between 3.0 T and 7.0 T measurements (p = 0.379). We found a decrease in standard deviation from our original angiography analysis software (QMra) to a newer (LAVA) software package (p < 0.001). Furthermore, we found that the dilation after sildenafil and calcitonin gene-related peptide were comparable between 3.0 T and 7.0 T. CONCLUSIONS: Our findings suggest no gain from the increase in voxel resolution but cemented dilatory findings from earlier. The implemented software update improved variance in circumference measurements in the intradural middle meningeal artery, which should be exploited in future studies. TRIAL REGISTRATION: The study is part of a parent study, which is registered at ClinicalTrials.gov ( NCT03143465 ).

Investigating macrophage-mediated inflammation in migraine using ultrasmall superparamagnetic iron oxide-enhanced 3T magnetic resonance imaging.

BACKGROUND: Initiating mechanisms of migraine headache remain poorly understood and a biomarker of migraine does not exist. Inflammation pertaining to the wall of cerebral arteries and brain parenchyma has been suggested to play a role in migraine pathophysiology. OBJECTIVE: We conducted the first experimental human study to investigate macrophage-mediated inflammation as a possible biomarker of migraine. METHODS: Using ultrasmall superparamagnetic iron oxide (USPIO)-enhanced 3T magnetic resonance imaging (MRI), we investigated the presence of macrophages in cerebral artery walls and in brain parenchyma of patients with migraine without aura. We used the phosphodiesterase-3-inhibitor cilostazol as an experimental migraine trigger, and investigated both patients who received sumatriptan treatment, and patients who did not. To validate our use of USPIO-enhanced MRI, we included a preclinical mouse model with subcutaneous capsaicin injection in the trigeminal V1 area. The study is registered at ClinicalTrials.gov with the identifier NCT02549898. RESULTS: A total of 28 female patients with migraine without aura underwent a baseline MRI scan, ingested cilostazol, developed a migraine-like attack, and underwent an USPIO-enhanced MRI scan > 24 hours after intravenous administration of USPIO. Twelve patients treated their attack with 6 mg s.c. sumatriptan, while the remaining 16 patients received no migraine-specific rescue medication. The preclinical model confirmed that USPIO-enhanced MRI detects macrophage-mediated inflammation. In patients, however, migraine attacks were not associated with increased USPIO signal on the pain side of the head compared to the non-pain side. CONCLUSION: Our findings suggest that migraine without aura is not associated with macrophage-mediated inflammation specific to the head pain side.

Correction to: Ultra-high field MR angiography in human migraine models: a 3.0 T/7.0 T comparison study.

After publication of the original article [1], the authors have notified us that an updated version of Figures 1, 2 and 3 should have been published. The incorrect and revised figures can be found below.

Cardiac perfusion and function after high-intensity exercise training in late premenopausal and recent postmenopausal women: an MRI study.

We examined the influence of recent menopause and aerobic exercise training in women on myocardial perfusion, left ventricular (LV) dimension, and function. Two groups (n = 14 each) of healthy late premenopausal (50.2 ± 2.1 yr) and recent postmenopausal (54.2 ± 2.8 yr) women underwent cardiac magnetic resonance imaging (cMRI) at baseline and after 12 wk of high-intensity aerobic training. Measurements included LV morphology, systolic function, and myocardial perfusion at rest and during an adenosine stress test. At baseline, resting myocardial perfusion was lower in the postmenopausal than the premenopausal group (77 ± 3 vs. 89 ± 3 ml·100 g-1·min-1; P = 0.01), while adenosine-induced myocardial perfusion was not different (P = 0.81). After exercise training, resting myocardial perfusion was lower in both groups (66 ± 2; P = 0.002 vs. 81 ± 3 ml·100 g-1·min-1; P = 0.03). The adenosine-induced change in myocardial perfusion was lower in the groups combined (by 402 ± 17 ml·100 g-1·min-1; P = 0.02), and the adenosine-induced increase in heart rate was 10 ± 2 beats/min lower (P < 0.0001) in both groups after training. Normalization of myocardial perfusion using an estimate of cardiac work eliminated the differences in perfusion between the premenopausal and postmenopausal groups and the effect of training. Left ventricle mass was higher in both groups (P = 0.03; P = 0.006), whereas LV end-diastolic (P = 0.02) and stroke (P = 0.045) volumes were higher in the postmenopausal group after training. Twelve weeks of exercise training increased left ventricle mass and lowered resting and adenosine-induced myocardial perfusion, an effect that was likely related to cardiac work. The current data also suggest that the early menopausal transition has limited impact on cardiac function and structure. NEW & NOTEWORTHY This study provides for the first time estimates of myocardial perfusion in late premenopausal and recent postmenopausal women before and after a period of intense aerobic training. Resting myocardial perfusion was lower in postmenopausal than premenopausal women. Training lowered myocardial resting and stress perfusion in both groups, an effect that was likely influenced by the lower heart rate.

Sildenafil and calcitonin gene-related peptide dilate intradural arteries: A 3T MR angiography study in healthy volunteers.

BACKGROUND: Sildenafil and calcitonin gene-related peptide are vasoactive substances that induce migraine attacks in patients. The intradural arteries are thought to be involved, but these have never been examined in vivo. Sildenafil is the only migraine-inducing compound for which cephalic, extracranial artery dilation is not reported. Here, we investigate the effects of sildenafil and calcitonin gene-related peptide on the extracranial and intradural parts of the middle meningeal artery. METHODS: In a double-blind, randomized, three-way crossover, placebo-controlled head-to-head comparison study, MR-angiography was recorded in healthy volunteers at baseline and twice after study drug (sildenafil/ calcitonin gene-related peptide/saline) administration. Circumferences of extracranial and intradural middle meningeal artery segments were measured using semi-automated analysis software. The area under the curve for circumference change was compared using paired t-tests between study days. RESULTS: Twelve healthy volunteers completed the study. The area under the curveBaseline-120min was significantly larger on both the sildenafil and the calcitonin gene-related peptide day in the intradural middle meningeal artery (calcitonin gene-related peptide, p = 0.013; sildenafil, p = 0.027) and the extracranial middle meningeal artery (calcitonin gene-related peptide, p = 0.0003; sildenafil, p = 0.021), compared to placebo. Peak intradural middle meningeal artery dilation was 9.9% (95% CI [2.9-16.9]) after sildenafil (T30min) and 12.5% (95% CI [8.1-16.8]) after calcitonin gene-related peptide (T30min). Peak dilation of the extracranial middle meningeal artery after calcitonin gene-related peptide (T30min) was 15.7% (95% CI [11.2-20.1]) and 18.9% (95% CI [12.8-24.9]) after sildenafil (T120min). CONCLUSION: An important novel finding is that both sildenafil and calcitonin gene-related peptide dilate intradural arteries, supporting the notion that all known pharmacological migraine triggers dilate cephalic vessels. We suggest that intradural artery dilation is associated with headache induced by calcitonin gene-related peptide and sildenafil.