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.

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.

Single-Voxel MR Spectroscopy of Gliomas with s-LASER at 7T.

BACKGROUND AND PURPOSE: Magnetic resonance spectroscopy (MRS)-a method of analysing metabolites in vivo-has been utilized in several studies of brain glioma biomarkers at lower field strengths. At ultra-high field strengths, MRS provides an improved signal-to-noise-ratio and spectral resolution, but 7T studies on patients with gliomas are sparse. The purpose of this exploratory study was to evaluate the potential clinical implication of the use of single-voxel MRS at 7T to assess metabolic information on lesions in a pilot cohort of patients with grade II and III gliomas. METHODS: We scanned seven patients and seven healthy controls using the semi-localization by adiabatic-selective refocusing sequence on a Philips Achieva 7T system with a standard dual-transmit head coil. The metabolic ratios were calculated relative to water and total creatine. Additionally, 2-hydroxyglutarate (2-HG) MRS was carried out in four of the patients, and the 2-HG concentration was calculated relative to water. RESULTS: When comparing the tumour data to control regions in both patients and healthy controls, we found that the choline/creatine and myo-inositol/creatine ratios were significantly increased and that the N-acetylaspartate/creatine and the neurotransmitter glutamate/creatine ratios were significantly decreased. The N-acetylaspartate/water and glutamate/water ratios were also significantly decreased. The lactate/water and lactate/creatine ratios showed increases, although not significant. The GABA/water ratio was significantly decreased, but the GABA/creatine ratio was not. MRS spectra showed the presence of 2-HG in three of the four patients studied. Three of the patients, including the MRS 2-HG-negative patient, were operated on, and all of them had the IDH mutation. CONCLUSION: Our findings were consistent with the existing literature on 3T and 7T MRS.

GLP-1 Promotes Cortical and Medullary Perfusion in the Human Kidney and Maintains Renal Oxygenation During NaCl Loading.

Background GLP-1 (glucagon-like peptide-1) receptor agonists exert beneficial long-term effects on cardiovascular and renal outcomes. In humans, the natriuretic effect of GLP-1 depends on GLP-1 receptor interaction, is accompanied by suppression of angiotensin II, and is independent of changes in renal plasma flow. In rodents, angiotensin II constricts vasa recta and lowers medullary perfusion. The current randomized, controlled, crossover study was designed to test the hypothesis that GLP-1 increases renal medullary perfusion in healthy humans. Methods and Results Healthy male participants (n=10, aged 27±4 years) ingested a fixed sodium intake for 4 days and were examined twice during a 1-hour infusion of either GLP-1 (1.5 pmol/kg per minute) or placebo together with infusion of 0.9% NaCl (750 mL/h). Interleaved measurements of renal arterial blood flow, oxygenation (R2*), and perfusion were acquired in the renal cortex and medulla during infusions, using magnetic resonance imaging. GLP-1 infusion increased medullary perfusion (32±7%, P<0.001) and cortical perfusion (13±4%, P<0.001) compared with placebo. Here, NaCl infusion decreased medullary perfusion (-5±2%, P=0.007), whereas cortical perfusion remained unchanged. R2* values increased by 3±2% (P=0.025) in the medulla and 4±1% (P=0.008) in the cortex during placebo, indicative of decreased oxygenation, but remained unchanged during GLP-1. Blood flow in the renal artery was not altered significantly by either intervention. Conclusions GLP-1 increases predominantly medullary but also cortical perfusion in the healthy human kidney and maintains renal oxygenation during NaCl loading. In perspective, suppression of angiotensin II by GLP-1 may account for the increase in regional perfusion. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04337268.

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.

New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary.

Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication were the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013. The proposal of these hallmarks of ageing has been instrumental in guiding and pushing forward research on the biology of ageing. In the nearly past 10 years, our in-depth exploration on ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones. Amalgamation of the 'old' and 'new' hallmarks of ageing may provide a more comprehensive explanation of ageing and age-related diseases, shedding light on interventional and therapeutic studies to achieve healthy, happy, and productive lives in the elderly.

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.

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.

Effects of prenatal nutrient supplementation and early life exposures on neurodevelopment at age 10: a randomised controlled trial - the COPSYCH study protocol.

INTRODUCTION: Nutrient deficiency and immune and inflammatory disturbances in early life may compromise neurodevelopment and be implicated in the aetiology of psychiatric disorders. However, current evidence is limited by its predominantly observational nature. COpenhagen Prospective Study on Neuro-PSYCHiatric Development (COPSYCH) is a research alliance between Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research with the overall aim to investigate effects of prenatal and early life exposures on neurodevelopment at 10 years. COPSYCH will investigate the impact of prenatal n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) and high-dose vitamin D supplementation on neurodevelopment reflected by brain development, neurocognition and psychopathology. Moreover, the neurodevelopmental impact of early life exposures such as infections, low grade inflammation and the gut microbiome will be scrutinised. METHODS AND ANALYSIS: COPSYCH is based on the prospective and ongoing COPSAC2010 birth cohort of 700 mother-child pairs. Randomised controlled trials of supplementation with n-3 LCPUFA and/or high-dose vitamin D or placebo in the third trimester were embedded in a factorial 2×2 design (ClinicalTrials.gov: NCT01233297 and NCT00856947). This unique cohort provides deep phenotyping data from 14 previous clinical follow-up visits and exposure assessments since birth. The ongoing 10-year visit is a 2-day visit. Day 1 includes a comprehensive neurocognitive examination, and assessment of psychopathological dimensions, and assessment of categorical psychopathology. Day 2 includes acquisition of brain structural, diffusion and functional sequences using 3 Tesla MRI. Study outcomes are neurocognitive, psychopathological and MRI measures. ETHICS AND DISSEMINATION: This study has been approved by the Danish National Committee on Health Research Ethics and The Danish Data Protection Agency. The study is conducted in accordance with the guiding principles of the Declaration of Helsinki. Parents gave written informed consent before enrolment.

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.