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.

Arterial Spin Labeling Magnetic Resonance Imaging for Acute Disorders of Consciousness in the Intensive Care Unit.

BACKGROUND: To investigate patients with disorders of consciousness (DoC) for residual awareness, guidelines recommend quantifying glucose brain metabolism using positron emission tomography. However, this is not feasible in the intensive care unit (ICU). Cerebral blood flow (CBF) assessed by arterial spin labeling magnetic resonance imaging (ASL-MRI) could serve as a proxy for brain metabolism and reflect consciousness levels in acute DoC. We hypothesized that ASL-MRI would show compromised CBF in coma and unresponsive wakefulness states (UWS) but relatively preserved CBF in minimally conscious states (MCS) or better. METHODS: We consecutively enrolled ICU patients with acute DoC and categorized them as being clinically unresponsive (i.e., coma or UWS [≤ UWS]) or low responsive (i.e., MCS or better [≥ MCS]). ASL-MRI was then acquired on 1.5 T or 3 T. Healthy controls were investigated with both 1.5 T and 3 T ASL-MRI. RESULTS: We obtained 84 ASL-MRI scans from 59 participants, comprising 36 scans from 35 patients (11 women [31.4%]; median age 56 years, range 18-82 years; 24 ≤ UWS patients, 12 ≥ MCS patients; 32 nontraumatic brain injuries) and 48 scans from 24 healthy controls (12 women [50%]; median age 50 years, range 21-77 years). In linear mixed-effects models of whole-brain cortical CBF, patients had 16.2 mL/100 g/min lower CBF than healthy controls (p = 0.0041). However, ASL-MRI was unable to discriminate between ≤ UWS and ≥ MCS patients (whole-brain cortical CBF: p = 0.33; best hemisphere cortical CBF: p = 0.41). Numerical differences of regional CBF in the thalamus, amygdala, and brainstem in the two patient groups were statistically nonsignificant. CONCLUSIONS: CBF measurement in ICU patients using ASL-MRI is feasible but cannot distinguish between the lower and the upper ends of the acute DoC spectrum. We suggest that pilot testing of diagnostic interventions at the extremes of this spectrum is a time-efficient approach in the continued quest to develop DoC neuroimaging markers in the ICU.

Reproducibility and Optimal Arterial Input Function Selection in Dynamic Contrast-Enhanced Perfusion MRI in the Healthy Brain.

BACKGROUND: Dynamic contrast-enhanced MRI (DCE-MRI) has seen increasing use for quantification of low level of blood-brain barrier (BBB) leakage in various pathological disease states and correlations with clinical outcomes. However, currently there exists limited studies on reproducibility in healthy controls, which is important for the establishment of a normality threshold for future research. PURPOSE: To investigate the reproducibility of DCE-MRI and to evaluate the effect of arterial input function (AIF) selection and manual region of interests (ROI) delineation vs. automated global segmentation. STUDY TYPE: Prospective. POPULATION: A total of 16 healthy controls; 11 females; mean age 28.7 years (SD 10.1). FIELD STRENGTH/SEQUENCE: A 3T; GE DCE; 3D TFE T1WI. 2D TSE T2. ASSESSMENT: The influx constant Ki , a measure of BBB permeability, and Vp , the blood plasma volume, was calculated using the Patlak model. Cerebral blood flow (CBF) was calculated using Tikhonov model free deconvolution. Manual tissue ROIs, drawn by H.J.S. (30+ years of experience), were compared to automatic tissue segmentation. STATISTICAL TESTS: Intraclass correlation coefficient (ICC) and repeatability coefficient (RC) was used to assess reproducibility. Bland-Altman plots were used to evaluate agreement between measurements day 1 vs. day 2, and manual vs. segmentation method. RESULTS: Ki showed excellent reproducibility in both white and gray matter with an ICC between 0.79 and 0.82 and excellent agreement between manual ROI and automatic segmentation, with an ICC of 0.89 for Ki in WM. Furthermore, Ki values in gray and white matter conforms with histological tissue characteristics, where gray matter generally has a 2-fold higher vessel density. The highest reproducibility measures of Ki (ICC = 0.83), CBF (ICC = 0.77) and Vd (ICC = 0.83) was obtained with the AIF sampled in the internal carotid artery (ICA). DATA CONCLUSION: DCE-MRI shows excellent reproducibility of pharmacokinetic variables derived from healthy controls. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

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.

Human Cerebral Perfusion, Oxygen Consumption, and Lactate Production in Response to Hypoxic Exposure.

Exposure to moderate hypoxia in humans leads to cerebral lactate production, which occurs even when the cerebral metabolic rate of oxygen (CMRO2) is unaffected. We searched for the mechanism of this lactate production by testing the hypothesis of upregulation of cerebral glycolysis mediated by hypoxic sensing. Describing the pathways counteracting brain hypoxia could help us understand brain diseases associated with hypoxia. A total of 65 subjects participated in this study: 30 subjects were exposed to poikilocapnic hypoxia, 14 were exposed to isocapnic hypoxia, and 21 were exposed to carbon monoxide (CO). Using this setup, we examined whether lactate production reacts to an overall reduction in arterial oxygen concentration or solely to reduced arterial oxygen partial pressure. We measured cerebral blood flow (CBF), CMRO2, and lactate concentrations by magnetic resonance imaging and spectroscopy. CBF increased (P < 10-4), whereas the CMRO2 remained unaffected (P > 0.076) in all groups, as expected. Lactate increased in groups inhaling hypoxic air (poikilocapnic hypoxia: $0.0136\ \frac{\mathrm{mmol}/\mathrm{L}}{\Delta{\mathrm{S}}_{\mathrm{a}}{\mathrm{O}}_2}$, P < 10-6; isocapnic hypoxia: $0.0142\ \frac{\mathrm{mmol}/\mathrm{L}}{\Delta{\mathrm{S}}_{\mathrm{a}}{\mathrm{O}}_2}$, P = 0.003) but was unaffected by CO (P = 0.36). Lactate production was not associated with reduced CMRO2. These results point toward a mechanism of lactate production by upregulation of glycolysis mediated by sensing a reduced arterial oxygen pressure. The released lactate may act as a signaling molecule engaged in vasodilation.

White matter hyperintensities and cerebral microbleeds in persistent post-traumatic headache attributed to mild traumatic brain injury: a magnetic resonance imaging study.

OBJECTIVE: To examine whether white matter hyperintensities (WMHs) and cerebral microbleeds (CMBs) are more prevalent in people with persistent post-traumatic headache attributed to mild traumatic brain injury (TBI), compared with healthy controls. METHODS: A magnetic resonance imaging (MRI) study of adults with persistent post-traumatic headache attributed to mild TBI and age- and gender-matched healthy controls. A semi-structured interview and validated self-report instruments were used to record data on demographics, clinical characteristics, and comorbidities. Imaging data were obtained on a 3T MRI Scanner using a 32-channel head coil. Participants and controls underwent a single MRI session, in which fluid-attenuated inversion recovery was used to visualize WMHs, and susceptibility-weighted imaging was used to detect CMBs. The primary outcomes were (I) the difference in the mean number of WMHs between participants with persistent post-traumatic headache and healthy controls and (II) the difference in the mean number of CMBs between participants with persistent post-traumatic headache and healthy controls. All images were examined by a certified neuroradiologist who was blinded to the group status of the participants and controls. RESULTS: A total of 97 participants with persistent post-traumatic headache and 96 age- and gender-matched healthy controls provided imaging data eligible for analyses. Among 97 participants with persistent post-traumatic headache, 43 (44.3%) participants presented with ≥ 1 WMH, and 3 (3.1%) participants presented with ≥ 1 CMB. Compared with controls, no differences were found in the mean number of WMHs (2.7 vs. 2.1, P = 0.58) and the mean number of CMBs (0.03 vs. 0.04, P = 0.98). CONCLUSIONS: WMHs and CMBs were not more prevalent in people with persistent post-traumatic headache than observed in healthy controls. Future studies should focus on other MRI techniques to identify radiologic biomarkers of post-traumatic headache.

Visual stimuli induce serotonin release in occipital cortex: A simultaneous positron emission tomography/magnetic resonance imaging study.

Endogenous serotonin (5-HT) release can be measured noninvasively using positron emission tomography (PET) imaging in combination with certain serotonergic radiotracers. This allows us to investigate effects of pharmacological and nonpharmacological interventions on brain 5-HT levels in living humans. Here, we study the neural responses to a visual stimulus using simultaneous PET/MRI. In a cross-over design, 11 healthy individuals were PET/MRI scanned with the 5-HT1B receptor radioligand [11 C]AZ10419369, which is sensitive to changes in endogenous 5-HT. During the last part of the scan, participants either viewed autobiographical images with positive valence (n = 11) or kept their eyes closed (n = 7). The visual stimuli increased cerebral blood flow (CBF) in the occipital cortex, as measured with pseudo-continuous arterial spin labeling. Simultaneously, we found decreased 5-HT1B receptor binding in the occipital cortex (-3.6 ± 3.6%), indicating synaptic 5-HT release. Using a linear regression model, we found that the change in 5-HT1B receptor binding was significantly negatively associated with change in CBF in the occipital cortex (p = .004). For the first time, we here demonstrate how cerebral 5-HT levels change in response to nonpharmacological stimuli in humans, as measured with PET. Our findings more directly support a link between 5-HT signaling and visual processing and/or visual attention.

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.

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.

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 ).

Brain capillary transit time heterogeneity in healthy volunteers measured by dynamic contrast-enhanced T1 -weighted perfusion MRI.

PURPOSE: Capillary transit time heterogeneity, measured as CTH, may set the upper limit for extraction of substances in brain tissue, e.g., oxygen. The purpose of this study was to investigate the feasibility of dynamic contrast-enhanced T1 weighted MRI (DCE-MRI) at 3 Tesla (T), in estimating CTH based on a gamma-variate model of the capillary transit time distribution. In addition, we wanted to investigate if a subtle increase of the blood-brain barrier permeability can be incorporated into the model, still allowing estimation of CTH. MATERIALS AND METHODS: Twenty-three healthy subjects were scanned at 3.0T MRI system applying DCE-MRI and using a gamma-variate model to estimate CTH as well as cerebral blood flow (CBF), cerebral blood volume (CBV), and permeability of the blood-brain barrier, measured as the influx constant Ki . For proof of principle we also investigated three patients with recent thromboembolic events and a patient with a high grade brain tumor. RESULTS: In the healthy subjects, we found a narrow symmetric delta-like capillary transit time distribution in basal ganglia gray matter with median CTH of 0.93 s and interquartile range of 1.33 s. The corresponding residue impulse response function was compatible with the adiabatic tissue homogeneity model. In two patients with complete occlusion of the internal carotid artery and in the patient with a brain tumor CTH was increased with values up to 6 s in the affected brain tissue, with an exponential like residue impulse response function. CONCLUSION: Our results open the possibility of characterizing brain perfusion by the capillary transit time distribution using DCE-MRI, theoretically a determinant of efficient blood to brain transport of important substances. LEVEL OF EVIDENCE: 2 J. MAGN. RESON. IMAGING 2017;45:1809-1820.

Comparison of global cerebral blood flow measured by phase-contrast mapping MRI with 15 O-H2 O positron emission tomography.

PURPOSE: To compare mean global cerebral blood flow (CBF) measured by phase-contrast mapping magnetic resonance imaging (PCM MRI) and by 15 O-H2 O positron emission tomography (PET) in healthy subjects. PCM MRI is increasingly being used to measure mean global CBF, but has not been validated in vivo against an accepted reference technique. MATERIALS AND METHODS: Same-day measurements of CBF by 15 O-H2 O PET and subsequently by PCM MRI were performed on 22 healthy young male volunteers. Global CBF by PET was determined by applying a one-tissue compartment model with measurement of the arterial input function. Flow was measured in the internal carotid and vertebral arteries by a noncardiac triggered PCM MRI sequence at 3T. The measured flow was normalized to total brain weight determined from a volume-segmented 3D T1 -weighted anatomical MR-scan. RESULTS: Mean CBF was 34.9 ± 3.4 mL/100 g/min measured by 15 O-H2 O PET and 57.0 ± 6.8 mL/100 g/min measured by PCM MRI. The measurements were highly correlated (P = 0.0008, R2 = 0.44), although values obtained by PCM MRI were higher compared to 15 O-H2 O PET (absolute and relative differences were 22.0 ± 5.2 mL/100 g/min and 63.4 ± 14.8%, respectively). CONCLUSION: This study confirms the use of PCM MRI for quantification of global CBF, but also that PCM MRI systematically yields higher values relative to 15 O-H2 O PET, probably related to methodological bias. LEVEL OF EVIDENCE: 3 J. Magn. Reson. Imaging 2017;45:692-699.

Effect of sildenafil on skeletal and cardiac muscle in Becker muscular dystrophy.

OBJECTIVE: Patients with Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy lack neuronal nitric oxide synthase (nNOS). nNOS mediates physiological sympatholysis, thus ensuring adequate blood supply to working muscle. In mice lacking dystrophin, restoration of nNOS effects by a phosphodiesterase 5 (PDE5) inhibitor (sildenafil) improves skeletal and cardiac muscle performance. Sildenafil also improves blood flow in patients with BMD. We therefore hypothesized that sildenafil would improve blood flow, maximal work capacity, and heart function in patients with BMD. METHODS: A randomized, double-blind, placebo-controlled crossover design with two 4-week periods of treatment, separated by 2-week washout was used. We assessed brachial artery blood flow during maximal handgrip exercise, 6-minute walk test, maximal oxidative capacity, and life quality; cardiac function was evaluated by magnetic resonance imaging (MRI) at rest and during maximal handgrip exercise. Muscle nNOS and PDE5 were tested with Western blotting in 5 patients. RESULTS: Sixteen patients completed all skeletal muscle evaluations, and 13 completed the cardiac MRI investigations. Sildenafil had no effect on any of the outcome parameters. No serious adverse effects were recorded. PDE5 and nNOS were deficient in 5 of 5 biopsies. INTERPRETATION: Despite positive evidence from animal models of dystrophinopathy and physiological findings in patients with BMD, this double-blind, placebo-controlled clinical study showed no effect of sildenafil on blood flow, maximal work capacity, and heart function in adults with BMD. This discrepancy may be explained by a significant downregulation of PDE5 in muscle.

Age-related decline in cerebral oxygen consumption in multiple sclerosis.

Cerebral oxygen metabolism is altered in relapsing-remitting multiple sclerosis (RRMS), possibly a result of disease related cerebral atrophy with subsequent decreased oxygen demand. However, MS inflammation can also inhibit brain metabolism. Therefore, we measured cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) using MRI phase contrast mapping and susceptibility-based oximetry in 44 patients with early RRMS and 36 healthy controls. Cerebral atrophy and white matter lesion load were assessed from high-resolution structural MRI. Expanded Disability Status Scale (EDSS) scores were collected from medical records. The CMRO2 was significantly lower in patients (-15%, p = 0.002) and decreased significantly with age in patients relative to the controls (-1.35 µmol/100 g/min/year, p = 0.036). The lower CMRO2 in RRMS was primarily driven by a higher venous oxygen saturation in the sagittal sinus (p = 0.007) and not a reduction in CBF (p = 0.69). There was no difference in cerebral atrophy between the groups, and no correlation between CMRO2 and MS lesion volume or EDSS score. Therefore, the progressive CMRO2 decline observed before the occurrence of significant cerebral atrophy and despite adequate CBF supports emerging evidence of dysfunctional cellular respiration as a potential pathogenic mechanism and therapeutic target in RRMS.

Automated Quantitative Image-Derived Input Function for the Estimation of Cerebral Blood Flow Using Oxygen-15-Labelled Water on a Long-Axial Field-of-View PET/CT Scanner.

The accurate estimation of the tracer arterial blood concentration is crucial for reliable quantitative kinetic analysis in PET. In the current work, we demonstrate the automatic extraction of an image-derived input function (IDIF) from a CT AI-based aorta segmentation subsequently resliced to a dynamic PET series acquired on a Siemens Vision Quadra long-axial field of view scanner in 10 human subjects scanned with [15O]H2O. We demonstrate that the extracted IDIF is quantitative and in excellent agreement with a delay- and dispersion-corrected sampled arterial input function (AIF). Perfusion maps in the brain are calculated and compared from the IDIF and AIF, respectively, showed a high degree of correlation. The results demonstrate the possibility of defining a quantitatively correct IDIF compared with AIFs from the new-generation high-sensitivity and high-time-resolution long-axial field-of-view PET/CT scanners.

Subclinical epileptiform discharges in Alzheimer's disease are associated with increased hippocampal blood flow.

BACKGROUND: In epilepsy, the ictal phase leads to cerebral hyperperfusion while hypoperfusion is present in the interictal phases. Patients with Alzheimer's disease (AD) have an increased prevalence of epileptiform discharges and a study using intracranial electrodes have shown that these are very frequent in the hippocampus. However, it is not known whether there is an association between hippocampal hyperexcitability and regional cerebral blood flow (rCBF). The objective of the study was to investigate the association between rCBF in hippocampus and epileptiform discharges as measured with ear-EEG in patients with Alzheimer's disease. Our hypothesis was that increased spike frequency may be associated with increased rCBF in hippocampus. METHODS: A total of 24 patients with AD, and 15 HC were included in the analysis. Using linear regression, we investigated the association between rCBF as measured with arterial spin-labelling MRI (ASL-MRI) in the hippocampus and the number of spikes/sharp waves per 24 h as assessed by ear-EEG. RESULTS: No significant difference in hippocampal rCBF was found between AD and HC (p-value = 0.367). A significant linear association between spike frequency and normalized rCBF in the hippocampus was found for patients with AD (estimate: 0.109, t-value = 4.03, p-value < 0.001). Changes in areas that typically show group differences (temporal-parietal cortex) were found in patients with AD, compared to HC. CONCLUSIONS: Increased spike frequency was accompanied by a hemodynamic response of increased blood flow in the hippocampus in patients with AD. This phenomenon has also been shown in patients with epilepsy and supports the hypothesis of hyperexcitability in patients with AD. The lack of a significant difference in hippocampal rCBF may be due to an increased frequency of epileptiform discharges in patients with AD. TRIAL REGISTRATION: The study is registered at clinicaltrials.gov (NCT04436341).

Capillary transit time heterogeneity inhibits cerebral oxygen metabolism in patients with reduced cerebrovascular reserve capacity from steno-occlusive disease.

The healthy cerebral perfusion demonstrates a homogenous distribution of capillary transit times. A disruption of this homogeneity may inhibit the extraction of oxygen. A high degree of capillary transit time heterogeneity (CTH) describes that some capillaries have very low blood flows, while others have excessively high blood flows and consequently short transit times. Very short transit times could hinder the oxygen extraction due to insufficient time for diffusion of oxygen into the tissue. CTH could be a consequence of cerebral vessel disease. We examined whether patients with cerebral steno-occlusive vessel disease demonstrate high CTH and if elevation of cerebral blood flow (CBF) by administration of acetazolamide (ACZ) increases the cerebral metabolic rate of oxygen (CMRO2), or if some patients demonstrate reduced CMRO2 related to detrimental CTH. Thirty-four patients and thirty-one healthy controls participated. Global CBF and CMRO2 were acquired using phase-contrast MRI. Regional brain maps of CTH were acquired using dynamic contrast-enhanced MRI. Patients with impaired cerebrovascular reserve capacity demonstrated elevated CTH and a significant reduction of CMRO2 after administration of ACZ, which could be related to high CTH. Impaired oxygen extraction from CTH could be a contributing part of the declining brain health observed in patients with cerebral vessel disease.

Changes in hippocampal volume during a preceding 10-year period do not correlate with cognitive performance and hippocampal blood‒brain barrier permeability in cognitively normal late-middle-aged men.

Hippocampal blood-brain barrier (BBB) permeability may increase in normal healthy ageing and contribute to neurodegenerative disease. To examine this hypothesis, we investigated the correlation between blood-brain barrier (BBB) permeability, regional brain volume, memory functions and health and lifestyle factors in The Metropolit 1953 Danish Male Birth Cohort. We used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with a gadolinium-based contrast agent to assess BBB permeability in 77 participants in the cohort. BBB permeability was measured as Ki values in the hippocampus, thalamus and white matter. Over a 10-year period, we observed progressive atrophy of both the left and right hippocampus (p = 0.001). There was no significant correlation between current BBB permeability and hippocampal volume, prior atrophy or cognition. The hippocampus volume ratio was associated with better visual and verbal memory scores (p < 0.01). Regional BBB differences revealed higher Ki values in the hippocampus and white matter than in the thalamus (p < 0.001). Participants diagnosed with type II diabetes had significantly higher BBB permeability in the white matter (p = 0.015) and thalamus (p = 0.016), which was associated with a higher Fazekas score (p = 0.024). We do not find evidence that BBB integrity is correlated with age-related hippocampal atrophy or cognitive functions. The association between diabetes, white matter hyperintensities and increased BBB permeability is consistent with the idea that cerebrovascular disease compromises BBB integrity. Our findings suggest that the hippocampus is particularly prone to age-related atrophy, which may explain some of the cognitive changes that accompany older age, but this prior atrophy is not correlated with current BBB permeability.

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.