This thesis aimed to explore biochemical processes related to migraine outside (interictal) and during upcoming attacks. Chapter 2 describes the biochemical profiling of plasma samples from... Show moreThis thesis aimed to explore biochemical processes related to migraine outside (interictal) and during upcoming attacks. Chapter 2 describes the biochemical profiling of plasma samples from interictal migraine patients and healthy controls from eight Dutch cohorts with a proton nuclear magnetic resonance based metabolomics platform. In Chapter 3 cerebrospinal fluid (CSF) and plasma samples from interictal migraine with and without aura patients and healthy volunteers, were profiled using an ultra-performance liquid chromatography mass spectrometry (UPLC-MS) platform for amine measurements, as multiple amines have been implicated in migraine pathophysiology. Alcoholic beverages are frequently reported migraine triggers. Chapter 4 assessed the potential of various alcohol beverages as a migraine attack trigger using a questionnaire study in a large cohort of migraine patients. In Chapter 5, the frequently used pharmacological migraine trigger glyceryl trinitrate (GTN) was studied in migraine patients and healthy controls to investigate whether previously reported premonitory symptoms are indeed specific to migraine patients. In Chapter 6 glutamate, glutamine, and GABA were assed in the visual cortex of migraine patients before and over the course of a GTN-provoked attack to detect possible involvement of the glutamatergic system in the onset of attacks using proton magnetic resonance spectroscopy. Show less
Lundell, H.; Najac, C.; Bulk, M.; Kan, H.E.; Webb, A.G.; Ronen, I. 2021
Double diffusion encoding (DDE) of the water signal offers a unique ability to separate the effect of microscopic anisotropic diffusion in structural units of tissue from the overall macroscopic... Show moreDouble diffusion encoding (DDE) of the water signal offers a unique ability to separate the effect of microscopic anisotropic diffusion in structural units of tissue from the overall macroscopic orientational distribution of cells. However, the specificity in detected microscopic anisotropy is limited as the signal is averaged over different cell types and across tissue compartments. Performing side-by-side water and metabolite DDE spectroscopic (DDES) experiments provides complementary measures from which intracellular and extracellular microscopic fractional anisotropies (mu FA) and diffusivities can be estimated. Metabolites are largely confined to the intracellular space and therefore provide a benchmark for intracellular mu FA and diffusivities of specific cell types. By contrast, water DDES measurements allow examination of the separate contributions to water mu FA and diffusivity from the intraand extracellular spaces, by using a wide range of b values to gradually eliminate the extracellular contribution. Here, we aimed to estimate tissue and compartment specific human brain microstructure by combining water and metabolites DDES experiments. We performed our DDES measurements in two brain regions that contain widely different amounts of white matter (WM) and gray matter (GM): parietal white matter (PWM) and occipital gray matter (OGM) in a total of 20 healthy volunteers at 7 Tesla. Metabolite DDES measurements were performed at b = 7199 s/mm(2), while water DDES measurements were performed with a range of b values from 918 to 7199 s/mm(2). The experimental framework we employed here resulted in a set of insights pertaining to the morphology of the intracellular and extracellular spaces in both gray and white matter. Results of the metabolite DDES experiments in both PWM and OGM suggest a highly anisotropic intracellular space within neurons and glia, with the possible exception of gray matter glia. The water mu FA obtained from the DDES results at high b values in both regions converged with that of the metabolite DDES, suggesting that the signal from the extracellular space is indeed effectively suppressed at the highest b value. The mu FA measured in the OGM significantly decreased at lower b values, suggesting a considerably lower anisotropy of the extracellular space in GM compared to WM. In PWM, the water mu FA remained high even at the lowest b value, indicating a high degree of organization in the interstitial space in WM. Tortuosity values in the cytoplasm for water and tNAA, obtained with correlation analysis of microscopic parallel diffusivity with respect to GM/WM tissue fraction in the volume of interest, are remarkably similar for both molecules, while exhibiting a clear difference between gray and white matter, suggesting a more crowded cytoplasm and more complex cytomorphology of neuronal cell bodies and dendrites in GM than those found in long-range axons in WM. Show less
Enhanced activity of the glutamatergic system has been linked to migraine pathophysiology. The present study aimed to assess the involvement of the glutamatergic system in the onset of attacks. We... Show moreEnhanced activity of the glutamatergic system has been linked to migraine pathophysiology. The present study aimed to assess the involvement of the glutamatergic system in the onset of attacks. We provoked attacks by infusion of glyceryl trinitrate (GTN; 0.5 mu g/kg/min over 20 min) in 24 female episodic migraineurs without aura and 13 female age-matched healthy controls. Over the course of a single day participants were scanned three times at fixed time slots (baseline before GTN infusion, 90 min and 270 min after start of GTN infusion). Single volume proton magnetic resonance spectra (H-1-MRS) were acquired at 7 Tesla from a volume of interest (VOI, 2x2x3 cm) in the visual cortex. We assessed the concentrations of glutamate, its major precursor glutamine, and its product gamma-aminobutyric acid (GABA) over the course of a provoked attack. The preictal state was defined as the period after GTN infusion until the migraine-like headache started, independent of possible experienced premonitory symptoms, and the ictal state was defined as the period with provoked migraine-like headache. Data were analyzed using a linear mixed-effect model for repeated measures. Glutamate and glutamine levels did not change from interictal to the preictal and ictal state. GABA levels increased from interictal towards the preictal state for migraine patients compared with healthy controls. We conclude that high resolution 7T MRS is able to show changes in the glutamatergic system towards a triggered migraine attack, by revealing an increased GABA concentration associated with the onset of a migraine attack. Show less
Het doel van dit proefschrift was daarom de onderliggende biochemische processen gerelateerd aan migraine te onderzoeken. Het eerste gedeelte (Hoofdstukken 2 en 3) beschrijft twee onderzoeken... Show moreHet doel van dit proefschrift was daarom de onderliggende biochemische processen gerelateerd aan migraine te onderzoeken. Het eerste gedeelte (Hoofdstukken 2 en 3) beschrijft twee onderzoeken waarin gekeken is naar de biochemische constitutie van de hersenen van migraine patiënten door middel van proton magnetische resonantie spectroscopie (1H-MRS) en diffusie gewogen spectroscopie (DWS). In het tweede gedeelte (Hoofdstukken 4 en 5) wordt een systematische review met meta-analyse beschreven om een overzicht te geven van eerdere inspanningen om in verschillende lichaamsvloeistoffen biochemische verschillen te detecteren die relevant zijn voor migraine. Daarnaast wordt er een studie beschreven waarin is gekeken naar biochemische verschillen in liquor van migraine patiënten en gezonde controles. In het derde gedeelte worden twee methodologische studies beschreven waarin (Hoofdstukken 6 en 7) de biochemische stabiliteit van liquor en het effect van vervuiling met ethanol werden onderzocht. Show less
Najac, C.; Branzoli, F.; Ronen, I.; Valette, J. 2016
The studies described in this thesis explored the effects of nutritional, exercise and pharmacological interventions on ectopic triglyceride accumulation in obese patients and/or patients with type... Show moreThe studies described in this thesis explored the effects of nutritional, exercise and pharmacological interventions on ectopic triglyceride accumulation in obese patients and/or patients with type 1 or type 2 diabetes mellitus (T2DM). Ectopic fat is defined as triglyceride (TG) storage in tissues, other than adipose tissue, such as the liver, heart and skeletal muscle. The focus of this thesis is on ectopic fat accumulation in two important organs: the liver and the heart. Studies in current thesis indeed have shown that lifestyle and pharmacological interventions can change ectopic triglyceride accumulation in (advanced) T2DM and is associated with changes in function. However, the notion emerges that the different fat compartments have differential regulation in relation to exercise, nutrition and pharmacological interventions. This points to different regulatory mechanisms involved in the accumulation and/or lipolysis of these fat compartments. Alternatively, it is possible that similar mechanisms are involved but with different dose-response relationships. These cannot be derived from the studies described in the current thesis because the aims of these studies were not focussed at these mechanisms underlying the dynamics of the individual fat depots. As patients with obesity and T2DM may have different ectopic fat distribution, this may also affect their (cardiac) risk profile. Manchann et al. already studied the effect of lifestyle intervention versus antidiabetic medication in patients with different fat distribution and found that this could predict intervention failure. More studies in these dynamics will hopefully lead to understanding from which treatments specific patient groups will benefit most. Show less
In this thesis we focused on the functional and metabolic consequences of myocardial triglyceride (TG) accumulation in healthy subjects and in patients with diabetes mellitus. Ectopic accumulation... Show moreIn this thesis we focused on the functional and metabolic consequences of myocardial triglyceride (TG) accumulation in healthy subjects and in patients with diabetes mellitus. Ectopic accumulation of TGs is associated with organ dysfunction in metabolic disease in experimental animal studies. These organs include the heart, the liver and skeletal muscle. For the heart,translational studies in humans are scarce, mainly due to the difficulty of the assessment of myocardial TG content in humans, in vivo. Therefore, it remains unclear to what extent the observations in animal experiments can be extended to humans. Furthermore, the physiological and pathophysiological relevance of myocardial TG accumulation for myocardial function is unknown. In Chapter 2 we describe a non-invasive method, using hydrogen 1 magnetic resonance spectroscopy (1HMRS), to accurately and reproducibly measure myocardial TG content in humans, in vivo. We observed improved spectral resolution and an improved intraclass correlation coefficient for the assessment of myocardial TG content when spectroscopic measurements were performed with respiratory motion correction compared to spectra obtained without respiratory motion compensation. Diabetes mellitus and obesity are associated with increased plasma non-esterified fatty acid (NEFA) levels, myocardial TG accumulation, and myocardial dysfunction. Because a very low-calorie diet (VLCD) also increases plasma NEFA levels, we studied the effect of a short-term VLCD on myocardial TG content and cardiac function in healthy subjects in Chapter 3. We found increased myocardial TG content and a decrease in left ventricular diastolic function. Moreover, hepatic TG content decreased, indicating organ-specific effects of a VLCD. In animal studies high plasma levels of NEFAs are associated with increased myocardial TG stores and impaired myocardial function. Caloric restriction increases the delivery of fatty acids to the myocardium. We have therefore evaluated the effects of progressive caloric restriction in healthy subjects in Chapter 4. Upon progressive caloric restriction we documented a dose-dependent increase in plasma levels of NEFAs and myocardial TG content, and a dose-dependent decrease in left ventricular diastolic function. Short-term high-fat diets increase TG content in skeletal muscle. Moreover, a high-fat diet induces myocardial TG accumulation and myocardial dysfunction in animal models. We studied the effects of a short-term high-fat diet in healthy individuals in Chapter 5. We found no changes in myocardial TG content and no effects on left ventricular function. However, hepatic TG content increased. The data document physiological and organ-specific adaptation of TG content during a high-fat diet. Myocardial metabolism in patients with type 2 diabetes mellitus (DM2) is heavily dependent on fatty acids. Furthermore, in animals and in humans this increased fatty acid reliability has been associated with structural changes in the diabetic myocardium and with myocardial dysfunction. Therefore we have evaluated the effects of a short-term VLCD in patients with DM2 in Chapter 6, to test the myocardial flexibility in these patients. We have shown that myocardial TGs increase after a VLCD, associated with a decrease in left ventricular diastolic function. Furthermore, anti-lipolytic therapy with acipimox during the VLCD prevented these changes in myocardial TG stores and myocardial function. Hepatic TG content was unchanged after both the interventions. The study illustrates the flexibility of myocardial TG stores and myocardial function in patients with DM2. Moreover, the data implicate the relevance of plasma NEFAs as mediators of the cardiac effects of a VLCD in patients with DM2. In Chapter 7 we evaluated the effects of therapeutic weight loss in obese, insulin-treated patients with DM2. Obesity and DM2 are major risk factors for cardiovascular disease, and prolonged caloric restriction has shown to induce weight loss and improve glycemic control. In this study we evaluated the effects of prolonged caloric restriction on myocardial and hepatic TG content and on myocardial function. Upon substantial weight loss there were considerable metabolic improvements in glucose and fat metabolism, associated with decreased myocardial TG content and a decrease in hepatic TG stores. Furthermore, myocardial diastolic function improved. The data show that in these obese patients with DM2, myocardial TG stores are flexible and amendable to therapeutic intervention by caloric restriction. Patients with type 1 diabetes mellitus (DM1) suffer from frequent episodes of hyperglycemic dysregulation, due to imperfections in exogenous insulin treatment, which mimics endogenous insulin secretion. These episodes of hyperglycemia are accompanied by perturbations in lipid metabolism as well. We have therefore evaluated the effects of controlled, short-term hyperglycemia in patients with DM1 in Chapter 8. Despite hyperglycemic dysregulation by partial insulin deprivation and the increase in plasma NEFA levels, myocardial TG content and myocardial function did not change. Apparently, the heart is protected from short-term metabolic effects of partial insulin deprivation in patients with DM1. In conclusion, myocardial TGs can be accurately measured in humans with 1HMRS. Myocardial TG stores are flexible in healthy subjects and in patients with DM2 upon differences in dietary nutritional intake. Changes in myocardial TG content are associated with changes in left ventricular function. Myocardial TGs reflect the discrepancy between fatty acid uptake and fatty acid oxidation and most likely reflect increased intracellular availability of fatty acid derivatives, which alter structure and function of the myocardium. Redistribution of TGs is tissue-specific, since TGs in the heart and the liver do not always show the same responses to physiological interventions. In patients with DM1, the heart is protected from short-term metabolic effects of hyperglycemic dysregulation, with respect to myocardial TG accumulation and alterations in myocardial function. Show less
Neuropsychiatric systemic lupus erythematosus (NPSLE) is a rheumatologic disorder causing neurologic, psychiatric and/or psychologic symptoms. The most important clinical problems are the aspecific... Show moreNeuropsychiatric systemic lupus erythematosus (NPSLE) is a rheumatologic disorder causing neurologic, psychiatric and/or psychologic symptoms. The most important clinical problems are the aspecific nature of signs and symptoms, the limited knowledge on pathogenesis and the absence of a diagnostic gold standard. Magnetic resonance imaging (MRI) is considered the most important imaging modality of the brain in NPSLE patients. Abnormalities visible on conventional MRI appear anywhere in the brain, and may normalize, stabilize or increase with loss of brain parenchyma. Apart from conventional MRI sequences, in this thesis advanced MRI techniques such as magnetization transfer imaging (MTI) were also applied, which are more sensitive to microscopic brain damage invisible to the human eye. Microscopic brain damage in NPSLE appears mostly in the cortical gray matter and is associated with the presence of anticardiolipin antibodies. The final brain damage, as observed using different MRI techniques, consists of neuronal and axonal damage, atrophy, demyelination and gliosis. Changes in the total amount of microscopic brain damage as detected by MTI correlate with changes in clinical status. This thesis contributes to the knowledge on the pathogenesis of NPSLE, and illustrates that advanced and conventional radiological techniques can be helpful in making diagnostic and therapeutic decisions. Show less
