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).

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.

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.

Early cerebral amyloid-ß accumulation and hypermetabolism are associated with subtle cognitive deficits before accelerated cerebral atrophy.

AIMS: Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta (Aß) in the brain. The deposition of Aß is believed to initiate a detrimental cascade, including cerebral hypometabolism, accelerated brain atrophy, and cognitive problems-ultimately resulting in AD. However, the timing and causality of the cascade resulting in AD are not yet fully established. Therefore, we examined whether early Aß accumulation affects cerebral glucose metabolism, atrophy rate, and age-related cognitive decline before the onset of neurodegenerative disease. METHODS: Participants from the Metropolit 1953 Danish Male Birth Cohort underwent brain positron emission tomography (PET) imaging using the radiotracers [11C]Pittsburgh Compound-B (PiB) (N = 70) and [18F]Fluorodeoxyglucose (FDG) (N = 76) to assess cerebral Aß accumulation and glucose metabolism, respectively. The atrophy rate was calculated from anatomical magnetic resonance imaging (MRI) scans conducted presently and 10 years ago. Cognitive decline was examined from neurophysiological tests conducted presently and ten or 5 years ago. RESULTS: Higher Aß accumulation in AD-critical brain regions correlated with greater visual memory decline (p = 0.023). Aß accumulation did not correlate with brain atrophy rates. Increased cerebral glucose metabolism in AD-susceptible regions correlated with worse verbal memory performance (p = 0.040). CONCLUSIONS: Aß accumulation in known AD-related areas was associated with subtle cognitive deficits. The association was observed before hypometabolism or accelerated brain atrophy, suggesting that Aß accumulation is involved early in age-related cognitive dysfunction. The association between hypermetabolism and worse memory performance may be due to early compensatory mechanisms adapting for malfunctioning neurons by increasing metabolism.

Patients with type 1 diabetes and albuminuria have a reduced brain glycolytic capability that is correlated with brain atrophy.

Introduction: Patients with type 1 diabetes (T1D) demonstrate brain alterations, including white matter lesions and cerebral atrophy. In this case-control study, we investigated if a reason for this atrophy could be because of diabetes-related complications affecting cerebrovascular or cerebral glycolytic functions. Cerebral physiological dysfunction can lead to energy deficiencies and, consequently, neurodegeneration. Methods: We examined 33 patients with T1D [18 females, mean age: 50.8 years (range: 26-72)] and 19 matched healthy controls [7 females, mean age: 45.0 years (range: 24-64)]. Eleven (33%) of the patients had albuminuria. Total brain volume, brain parenchymal fraction, gray matter volume and white matter volume were measured by anatomical MRI. Cerebral vascular and glycolytic functions were investigated by measuring global cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and cerebral lactate concentration in response to the inhalation of hypoxic air (12-14% fractional oxygen) using phase-contrast MRI and magnetic resonance spectroscopy (MRS) techniques. The inspiration of hypoxic air challenges both cerebrovascular and cerebral glycolytic physiology, and an impaired response will reveal a physiologic dysfunction. Results: Patients with T1D and albuminuria had lower total brain volume, brain parenchymal fraction, and gray matter volume than healthy controls and patients without albuminuria. The inhalation of hypoxic air increased CBF and lactate in all groups. Patients with albuminuria had a significantly (p = 0.032) lower lactate response compared to healthy controls. The CBF response was lower in patients with albuminuria compared to healthy controls, however not significantly (p = 0.24) different. CMRO2 was unaffected by the hypoxic challenge in all groups (p > 0.16). A low lactate response was associated with brain atrophy, characterized by reduced total brain volume (p = 0.003) and reduced gray matter volume (p = 0.013). Discussion: We observed a reduced response of the lactate concentration as an indication of impaired glycolytic activity, which correlated with brain atrophy. Inadequacies in upregulating cerebral glycolytic activity, perhaps from reduced glucose transporters in the brain or hypoxia-inducible factor 1 pathway dysfunction, could be a complication in diabetes contributing to the development of neurodegeneration and declining brain health.

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 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.

Cerebrovascular Reactivity and Neurovascular Coupling in Multiple Sclerosis-A Systematic Review.

The inflammatory processes observed in the central nervous system in multiple sclerosis (MS) could damage the endothelium of the cerebral vessels and lead to a dysfunctional regulation of vessel tonus and recruitment, potentially impairing cerebrovascular reactivity (CVR) and neurovascular coupling (NVC). Impaired CVR or NVC correlates with declining brain health and potentially plays a causal role in the development of neurodegenerative disease. Therefore, we examined studies on CVR or NVC in MS patients to evaluate the evidence for impaired cerebrovascular function as a contributing disease mechanism in MS. Twenty-three studies were included (12 examined CVR and 11 examined NVC). Six studies found no difference in CVR response between MS patients and healthy controls. Five studies observed reduced CVR in patients. This discrepancy can be because CVR is mainly affected after a long disease duration and therefore is not observed in all patients. All studies used CO2 as a vasodilating stimulus. The studies on NVC demonstrated diverse results; hence a conclusion that describes all the published observations is difficult to find. Future studies using quantitative techniques and larger study samples are needed to elucidate the discrepancies in the reported results.

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.

Interictal pontine metabolism in migraine without aura patients: A 3 Tesla proton magnetic resonance spectroscopy study.

In the pons, glutamatergic mechanisms are involved in regulating inhibitory descending pain modulation, serotoninergic neurotransmission as well as modulating the sensory transmission of the trigeminovascular system. Migraine involves altered pontine activation and structural changes, while biochemical, genetic and clinical evidence suggests that altered interictal pontine glutamate levels may be an important pathophysiological feature of migraine abetting to attack initiation. Migraine without aura patients were scanned outside attacks using a proton magnetic resonance spectroscopy protocol optimized for the pons at 3 Tesla. The measurements were performed on two separate days to increase accuracy and compared to similar repeated measurements in healthy controls. We found that interictal glutamate (i.e. Glx) levels in the pons of migraine patients (n = 33) were not different from healthy controls (n = 16) (p = 0.098), while total creatine levels were markedly increased in patients (9%, p = 0.009). There was no correlation of glutamate or total creatine levels to migraine frequency, days since the last attack, usual pain intensity of attacks or disease duration. In conclusion, migraine is not associated with altered interictal pontine glutamate levels. However, the novel finding of increased total creatine levels suggests that disequilibrium in the pontine energy metabolism could be an important feature of migraine pathophysiology.

Validation of kinetic modeling of [15O]H2O PET using an image derived input function on hybrid PET/MRI.

In present study we aimed to validate the use of image-derived input functions (IDIF) in the kinetic modeling of cerebral blood flow (CBF) measured by [15O]H2O PET by comparing with the accepted reference standard arterial input function (AIF). Additional comparisons were made to mean cohort AIF and CBF values acquired by methodologically independent phase-contrast mapping (PCM) MRI. Using hybrid PET/MRI an IDIF was generated by measuring the radiotracer concentration in the internal carotid arteries and correcting for partial volume effects using the intravascular volume measured from MRI-angiograms. Seven patients with carotid steno-occlusive disease and twelve healthy controls were examined at rest, after administration of acetazolamide, and, in the control group, during hyperventilation. Agreement between the techniques was examined by linear regression and Bland-Altman analysis. Global CBF values modeled using IDIF correlated with values from AIF across perfusion states in both patients (p<10-6, R2=0.82, 95% limits of agreement (LoA)=[-11.3-9.9] ml/100 g/min) and controls (p<10-6, R2=0.87, 95% LoA=[-17.1-13.7] ml/100 g/min). The reproducibility of gCBF using IDIF was identical to AIF (15.8%). Values from IDIF and AIF had equally good correlation to measurements by PCM MRI, R2=0.86 and R2=0.84, (p<10-6), respectively. Mean cohort AIF performed substantially worse than individual IDIFs (p<10-6, R2=0.63, LoA=[-12.8-25.3] ml/100 g/min). In the patient group, use of IDIF provided similar reactivity maps compared to AIF. In conclusion, global CBF values modeled using IDIF correlated with values modeled by AIF and similar perfusion deficits could be established in a patient group.

Glutamate levels and perfusion in pons during migraine attacks: A 3T MRI study using proton spectroscopy and arterial spin labeling.

Migraine is a complex disorder, involving peripheral and central brain structures, where mechanisms and site of attack initiation are an unresolved puzzle. While abnormal pontine neuronal activation during migraine attacks has been reported, exact implication of this finding is unknown. Evidence suggests an important role of glutamate in migraine, implying a possible association of pontine hyperactivity to increased glutamate levels. Migraine without aura patients were scanned during attacks after calcitonin gene-related peptide and sildenafil in a double-blind, randomized, double-dummy, cross-over design, on two separate study days, by proton magnetic resonance spectroscopy and pseudo-continuous arterial spin labeling at 3T. Headache characteristics were recorded until 24 h after drug administrations. Twenty-six patients were scanned during migraine, yielding a total of 41 attacks. Cerebral blood flow increased in dorsolateral pons, ipsilateral to pain side during attacks, compared to outside attacks (13.6%, p = 0.009). Glutamate levels in the same area remained unchanged during attacks (p = 0.873), while total creatine levels increased (3.5%, p = 0.041). In conclusion, dorsolateral pontine activation during migraine was not associated with higher glutamate levels. However, the concurrently increased total creatine levels may suggest an altered energy metabolism, which should be investigated in future studies to elucidate the role of pons in acute migraine.

Cerebrovascular effects of glibenclamide investigated using high-resolution magnetic resonance imaging in healthy volunteers.

Glibenclamide inhibits sulfonylurea receptor (SUR), which regulates several ion channels including SUR1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel and ATP-sensitive potassium (KATP) channel. Stroke upregulates SURl-TRPM4 channel, which causes a rapid edema formation and brain swelling. Glibenclamide may antagonize the formation of cerebral edema during stroke. Preclinical studies showed that glibenclamide inhibits KATP channel-induced vasodilation without altering the basal vascular tone. The in vivo human cerebrovascular effects of glibenclamide have not previously been investigated.In a randomized, double-blind, placebo-controlled, three-way cross-over study, we used advanced 3 T MRI methods to investigate the effects of glibenclamide and KATP channel opener levcromakalim on mean global cerebral blood flow (CBF) and intra- and extracranial artery circumferences in 15 healthy volunteers. Glibenclamide administration did not alter the mean global CBF and the basal vascular tone. Following levcromakalim infusion, we observed a 14% increase of the mean global CBF and an 8% increase of middle cerebral artery (MCA) circumference, and glibenclamide did not attenuate levcromakalim-induced vascular changes. Collectively, the findings demonstrate the vital role of KATP channels in cerebrovascular hemodynamic and indicate that glibenclamide does not inhibit the protective effects of KATP channel activation during hypoxia and ischemia-induced brain injury.

Feasibility of Glutamate and GABA Detection in Pons and Thalamus at 3T and 7T by Proton Magnetic Resonance Spectroscopy.

Glutamate detection in pons and thalamus using proton magnetic resonance spectroscopy (1H-MRS) after an intervention is of interest for studying various brain disorders. However, 1H-MRS in these brain regions is challenging and time-consuming, especially in longitudinal study designs. 1H-MRS of more cortical structures at the ultrahigh magnetic field strength of 7T yields an improved spectral output, including separation of the glutamate signal from the glutamine signal, in a shorter and more feasible scan time, as compared to conventional clinical field strengths. For this purpose, we compared the feasibility of 1H-MRS at 3T and 7T in pons and thalamus by applying a longitudinal study design of repeated measures on same day and three separate days at both field strength in five healthy participants. Total 1H-MRS acquisition time was reduced by a factor 3.75 for pons and by a factor 3 for thalamus at 7T as compared to 3T. We found higher spectral signal-to-noise ratio (SNR) (p < 0.001), lower linewidth (p = 0.001) and lower Cramér-Rao lower bounds (CRLB) (p < 0.001) for the combined glutamate and glutamine signal (Glx) in thalamus at 7T as compared to 3T. In pons, CRLB of Glx and SNR were lower at 7T (p = 0.002 and p = 0.006), with no differences in linewidth compared to 3T. Mean within-subject variability of Glx concentration estimates was lower at 7T compared to 3T for both pons and thalamus. At 7T, it was possible to assess glutamate and γ-aminobutyric acid (GABA) simultaneously in pons and thalamus. In conclusion, 1H-MRS at 7T resulted in improved spectral quality while allowing shorter scan times than at 3T as well as estimation of the pure glutamate signal in pons and thalamus. This opens up the opportunity for multimodal study designs and multiregional subcortical 1H-MRS research. Glutamate and GABA measurement at 7T in pons and thalamus is advantageous for future investigations of excitatory-inhibitory mechanisms in brain disorders.

PET imaging of meningioma with 18F-FLT: a predictor of tumour progression.

We have previously reported that PET with 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) provides a non-invasive assessment of cell proliferation in vivo in meningiomas. The purpose of this prospective study was to evaluate the potential of 18F-FLT PET in predicting subsequent tumour progression in asymptomatic meningiomas. Forty-three adult patients harbouring 46 MRI-presumed (n = 40) and residual meningiomas from previous surgery (n = 6) underwent a 60-min dynamic 18F-FLT PET scan prior to radiological surveillance. Maximum and mean tumour-to-blood ratios (TBRmax, TBRmean) of tracer radioactivity were calculated. Tumour progression was defined according to the latest published trial end-point criteria for bidimensional (2D) and corresponding yet exploratory volumetric measurements from the Response Assessment of Neuro-Oncology (RANO) workgroup. Independent-sample t-test, Pearson correlation coefficient, Cox regression, and receiver operating characteristic (ROC) curve analyses were used whenever appropriate. The median follow-up time after 18F-FLT PET imaging was 18 months (range 5-33.5 months). A high concordance rate (91%) was found with regard to disease progression using 2D-RANO (n = 11) versus volumetric criteria (n = 10). Using 2D-RANO criteria, 18F-FLT uptake was significantly increased in patients with progressive disease, compared to patients with stable disease (TBRmax, 5.5 ± 1.3 versus 3.6 ± 1.1, P < 0.0001; TBRmean, 3.5 ± 0.8 versus 2.4 ± 0.7, P < 0.0001). ROC analysis yielded optimal thresholds of 4.4 for TBRmax [sensitivity 82%, specificity 77%, accuracy 78%, and area under curve (AUC) 0.871; P < 0.0001] and 2.8 for TBRmean (sensitivity 82%, specificity 77%, accuracy 78%, AUC 0.848; P = 0.001) for early differentiation of patients with progressive disease from patients with stable disease. Upon excluding patients with residual meningioma or patients with stable disease with less than 12 months follow-up, the thresholds remained unchanged with similar diagnostic accuracies. Moreover, positive correlations were found between absolute and relative tumour growth rates and 18F-FLT uptake (r < 0.513, P < 0.015) that remained similar when excluding patients with residual meningioma or patients with stable disease and shorter follow-up period. Diagnostic accuracies were slightly inferior at 76% when assessing disease progression using volumetric criteria, while the thresholds remained unchanged. Multivariate analysis revealed that TBRmax was the only independent predictor of tumour progression (P < 0.046), while age, gender, baseline tumour size, tumour location, peritumoural oedema, and residual meningioma had no influence. The study reveals that 18F-FLT PET is a promising surrogate imaging biomarker for predicting subsequent tumour progression in treatment-naïve and asymptomatic residual meningiomas.

Pearls and Pitfalls in Interpretation of 68Ga-DOTATOC PET Imaging.

DOTA-D-Phe-Tyr-octreotide labeled with Ga (Ga-DOTATOC) is the commonly used PET tracer for imaging meningioma because of its high affinity to somatostatin receptor subtype 2 (SSTR2) and an established imaging modality for planning radiation and radionuclide therapy. However, SSTR2 is not an exclusive marker for meningioma, and not all meningiomas express high levels of SSTR2. The SSTR2 expression has been reported in other intracranial tumors, for example, glioma, pituitary adenoma, medullablastoma, primitive neuroectodermal tumors, and hemangioblastoma leading to a significant risk of misinterpretation of PET/CT findings. We present 2 cases with similar Ga-DOTATOC uptakes in 2 distinct etiologies, for example, cerebral lymphoma and meningioma.

Plasma Glucose Levels Increase During Spontaneous Attacks of Migraine With and Without Aura.

OBJECTIVE: To investigate plasma glucose changes during the ictal state of migraine compared to the interictal state. BACKGROUND: Previous studies suggest abnormal glucose metabolism in migraine patients during and outside of attacks. It is not known if plasma glucose levels change during spontaneous migraine attacks. METHODS: Plasma glucose levels were measured during and outside of spontaneous migraine attacks with and without aura. Plasma glucose values were corrected for diurnal variation of plasma glucose by subtracting the difference between the moving average (intervals of 2 hours) and overall mean from the plasma glucose values. RESULTS: This was a sub-study of a larger study conducted at Rigshospitalet Glostrup in the Capital Region of Denmark. Thirty-one patients (24 F, 7 M, 13 with aura, 18 without aura) were included in the study. Mean time from attack onset to blood sampling was 7.6 hours. Mean pain at the time of investigation was 6 on a 0-10 verbal rating scale. Plasma glucose was higher ictally compared to the interictal phase (interictal mean: 88.63 mg/dL, SD 11.70 mg/dL; ictal mean: 98.83 mg/dL, SD 13.16 mg/dL, difference 10.20 mg/dL, 95% CI = [4.30; 16.10]), P = .0014). The ictal increase was highest in patients investigated early during attacks and decreased linearly with time from onset of migraine (-1.57 mg/dL/hour from onset of attack, P = .020). The attack-related increase in blood glucose was not affected by pain intensity or presence of aura symptoms. CONCLUSIONS: We demonstrated higher plasma glucose values during spontaneous migraine attacks, independent of the presence of aura symptoms and not related to pain intensity, peaking in the early phase of attacks. Additional studies are necessary to confirm our findings and explore the possible underlying mechanisms.

Higher physiological vulnerability to hypoxic exposure with advancing age in the human brain.

The aging brain is associated with atrophy along with functional and metabolic changes. In this study, we examined age-related changes in resting brain functions and the vulnerability of brain physiology to hypoxic exposure in humans in vivo. Brain functions were examined in 81 healthy humans (aged 18-62 years) by acquisitions of gray and white matter volumes, cerebral blood flow, cerebral oxygen consumption, and concentrations of lactate, N-acetylaspartate, and glutamate+glutamine using magnetic resonance imaging and spectroscopy. We observed impaired cerebral blood flow reactivity in response to inhalation of hypoxic air (p = 0.029) with advancing age along with decreased cerebral oxygen consumption (p = 0.036), and increased lactate concentration (p = 0.009), indicating tissue hypoxia and impaired metabolism. Diminished resilience to hypoxia and consequently increased vulnerability to metabolic stress could be a key part of declining brain health with age. Furthermore, we observed increased resting cerebral lactate concentration with advancing age (p = 0.007), which might reflect inhibited brain clearance of waste products.

Comparison of simultaneous arterial spin labeling MRI and 15O-H2O PET measurements of regional cerebral blood flow in rest and altered perfusion states.

Arterial spin labelling (ASL) is a non-invasive magnetic resonance imaging (MRI) technique that may provide fully quantitative regional cerebral blood flow (rCBF) images. However, before its application in clinical routine, ASL needs to be validated against the clinical gold standard, 15O-H2O positron emission tomography (PET). We aimed to compare the two techniques by performing simultaneous quantitative ASL-MRI and 15O-H2O-PET examinations in a hybrid PET/MRI scanner. Duplicate rCBF measurements were performed in healthy young subjects (n = 14) in rest, during hyperventilation, and after acetazolamide (post-ACZ), yielding 63 combined PET/MRI datasets in total. Average global CBF by ASL-MRI and 15O-H2O-PET was not significantly different in any state (40.0 ± 6.5 and 40.6 ± 4.1 mL/100 g/min, respectively in rest, 24.5 ± 5.1 and 23.4 ± 4.8 mL/100 g/min, respectively, during hyperventilation, and 59.1 ± 10.4 and 64.7 ± 10.0 mL/100 g/min, respectively, post-ACZ). Overall, strong correlation between the two methods was found across all states (slope = 1.01, R2 = 0.82), while the correlations within individual states and of reactivity measures were weaker, in particular in rest (R2 = 0.05, p = 0.03). Regional distribution was similar, although ASL yielded higher perfusion and absolute reactivity in highly vascularized areas. In conclusion, ASL-MRI and 15O-H2O-PET measurements of rCBF are highly correlated across different perfusion states, but with variable correlation within and between hemodynamic states, and systematic differences in regional distribution.