Image-Derived Input Function for Human Brain Using High Resolution PET Imaging with [11C](R)-rolipram and [11C]PBR28

The aim of this study was to test seven previously published image-input methods in state-of-the-art high resolution PET brain images. Images were obtained with a High Resolution Research Tomograph plus a resolution-recovery reconstruction algorithm using two different radioligands with different radiometabolite fractions. Three of the methods required arterial blood samples to scale the image-input, and four were blood-free methods. values was quantified using a scoring system. Using the image input methods that gave the most accurate results with Logan analysis, we also performed kinetic modelling with a two-tissue compartment model.)-rolipram, which has a lower metabolite fraction. Compartment modeling gave less reliable results, especially for the estimation of individual rate constants.C]PBR28), the more difficult it is to obtain a reliable image-derived input function; and 4) in association with image inputs, graphical analyses should be preferred over compartmental modelling

Kinetic modelling of [(11)C]PBR28 for 18 kDa translocator protein PET data:A validation study of vascular modelling in the brain using XBD173 and tissue analysis

The 18 kDa translocator protein (TSPO) is a marker of microglia activation in the central nervous system and represents the main target of radiotracers for the in vivo quantification of neuroinflammation with positron emission tomography (PET). TSPO PET is methodologically challenging given the heterogeneous distribution of TSPO in blood and brain. Our previous studies with the TSPO tracers [11C]PBR28 and [11C]PK11195 demonstrated that a model accounting for TSPO binding to the endothelium improves the quantification of PET data. Here, we performed a validation of the kinetic model with the additional endothelial compartment through a displacement study. Seven subjects with schizophrenia, all high-affinity binders, underwent two [11C]PBR28 PET scans before and after oral administration of 90 mg of the TSPO ligand XBD173. The addition of the endothelial component provided a signal compartmentalization much more consistent with the underlying biology, as only in this model, the blocking study produced the expected reduction in the tracer concentration of the specific tissue compartment, whereas the non-displaceable compartment remained unchanged. In addition, we also studied TSPO expression in vessels using 3D reconstructions of histological data of frontal lobe and cerebellum, demonstrating that TSPO positive vessels account for 30% of the vascular volume in cortical and white matter

IMAGE DERIVED INPUT FUNCTION FOR BRAIN [11C]TMSX PET IMAGING

Modeling and analysis of positron emission tomography (PET) imaging data requires the critical information of the input function of the radioligand used. In PET imaging of the brain, the ‘gold standard’ for acquiring input function is to estimate the metabolite corrected arterial plasma input of the used radioligand as a function of time via arterial cannulation, i.e. to use the so-called original arterial input function (OAIF) method. Arterial cannulation, however, is unpleasant for the patient, invasive, requires expertise and additional resources. Consequently, it discourages patients and healthy subjects to enroll into clinical PET studies. To counter these problems, the feasibility of an alternative method for acquiring input function from the PET image, image-derived input function (IDIF), was evaluated for brain PET imaging with [11C]TMSX radioligand in this thesis. [11C]TMSX is a radioligand binding selectively to adenosine A2A-receptors. The method was implemented on data from 45 study subjects (9 healthy controls, 19 Parkinson’s disease patients and 17 multiple sclerosis patients) imaged with [11C]TMSX and High Resolution Research Tomograph (HRRT) PET scanner in earlier studies in Turku PET Centre. The results showed significant differences between the level of IDIF and OAIF values although with a high correlation. Image derived input function acquisition method that was used in this study is therefore not reliable enough to substitute original arterial input function. Alternative IDIF extraction methods should be investigated for this purpose in the future

Imaging of neuroinflammation in multiple sclerosis brain : a positron emission tomography and diffusion tensor imaging study

ABSTRACT Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, where the immune system attacks the protective myelin sheet surrounding the nerve cell axons, causing neuroinflammation and neurodegeneration. In this thesis, molecular and microstructural brain changes were evaluated in MS patients using diffusion tensor imaging (DTI) and positron emission tomography (PET) with translocator protein (TSPO) binding radioligand. In MS, TSPO is expressed mainly in activated microglia and therefore TSPO is considered as a marker of inflammation. The aim of this thesis was to evaluate the association between TSPO PET radioligand uptake and DTI macroparameters, as well as their association to clinical disability, in normal appearing white matter (NAWM). Moreover, the aim was to study if the individual physiological properties including age, body mass index (BMI) and sex have influence on the observed variability, which has been reported in previous clinical PET studies. The results showed that increased TSPO uptake in NAWM was associated with altered NAWM DTI macroparameters, their regional correspondence was consistent, and they both were associated with advanced clinical disability. Increased age was associated with higher TSPO uptake in NAWM and in thalamus of MS patients, whereas in healthy control subjects, higher age was associated with higher cortical TSPO uptake. However, a multicenter data analysis of healthy volunteers revealed that higher age was associated with higher cortical and subcortical TSPO uptake only in male subjects. Additionally, higher TSPO uptake was associated with lower BMI, and females showed higher TSPO uptake compared to males. The results demonstrate that PET and DTI can be used as complementary imaging modalities in clinical MS studies. TSPO levels may be associated with age, BMI and sex suggesting that they can be confounding factors in clinical designs. Subtle microglial activation may be initially related to normal ageing but is accentuated following neuroinflammation. ’ KEYWORDS: [11C](R)-PK11195, [11C]PBR28, ageing, body mass index, BMI, DTI, microglia, multiple sclerosis, PET, sex, TSPOTIIVISTELMÄ Multippeliskleroosi (MS-tauti) on keskushermoston autoimmuunisairaus, jossa immuunijärjestelmä hyökkää hermosoluja suojaavaa myeliiniä vastaan aiheuttaen tulehdusreaktiota ja hermosolujen rappeutumista. Tässä tutkimuksessa tarkasteltiin MS-tautiin liittyviä aivojen molekulaarisia ja rakenteellisia muutoksia käyttämällä diffuusiotensorikuvantamista (DTI) ja positroniemissiotomografiaa (PET) translokaattoriproteiiniin (TSPO) sitoutuvalla merkkiaineella. MS-taudissa TSPO esiintyy pääosin aktivoituneissa mikroglia-soluissa ja siksi sitä pidetään tulehdusreaktion markkerina. Tämän tutkimuksen tarkoituksena oli arvioida TSPO-sitoutumisen yhteyttä DTI-kuvantamisen makroparametreihin ja kummankin yhteyttä kliinisiin mittaustuloksiin. Koska aiemmissa kliinisissä tutkimuksissa on havaittu runsaasti yksilöllistä vaihtelua TSPO-sitoutumisessa, oli tavoitteena tarkastella yksilöllisten fysiologisten tekijöiden, kuten iän, painoindeksin ja sukupuolen yhteyttä TSPO-sitoutumiseen. Tulosten mukaan kohonnut TSPO-sitoutuminen terveessä valkeassa aineessa (NAWM) oli yhteydessä muuttuneisiin DTI-makroparametreihin, alueellinen vastaavuus oli yhtenevää ja kummankin menetelmän tulokset olivat yhteydessä kliinisiin mittaustuloksiin. Ikääntyminen oli yhteydessä kohonneeseen TSPO-sitou-tumiseen NAWM:ssa ja talamuksissa MS-potilailla, kun taas terveillä koehenkilöillä ikääntyminen oli yhteydessä korkeampaan kortikaaliseen TSPO-sitoutumiseen. Laajempi monikeskustutkimus osoitti kuitenkin, että ikääntyminen oli yhteydessä korkeampaan kortikaaliseen ja subkortikaaliseen TSPO-sitoutumiseen vain miehillä. Lisäksi korkeampi TSPO-sitoutuminen oli yhteydessä matalampaan painoindeksiin ja naisilla TSPO-sitoutuminen oli korkeampaa miehiin verrattuna. Tulokset osoittavat, että PET- ja DTI-kuvantaminen ovat toisiaan täydentäviä menetelmiä MS-taudin kuvantamisessa. Ikä, painoindeksi ja sukupuoli voivat olla sekoittavia tekijöitä kliinisissä TSPO-tutkimuksissa. TSPO-sitoutuminen liittyy normaaliin ikääntymiseen, mutta se korostuu tulehdusreaktion yhteydessä. AVAINSANAT: [11C](R)-PK11195, [11C]PBR28, DTI, ikääntyminen, mikroglia, MS-tauti, PET, painoindeksi, sukupuoli, TSP

Ovarian hormones shape brain structure, function, and chemistry: A neuropsychiatric framework for female brain health

There are robust sex differences in brain anatomy, function, as well as neuropsychiatric and neurodegenerative disease risk (1-6), with women approximately twice as likely to suffer from a depressive illness as well as Alzheimer’s Disease. Disruptions in ovarian hormones likely play a role in such disproportionate disease prevalence, given that ovarian hormones serve as key regulators of brain functional and structural plasticity and undergo major fluctuations across the female lifespan (7-9). From a clinical perspective, there is a wellreported increase in depression susceptibility and initial evidence for cognitive impairment or decline during hormonal transition states, such as the postpartum period and perimenopause (9-14). What remains unknown, however, is the underlying mechanism of how fluctuations in ovarian hormones interact with other biological factors to influence brain structure, function, and chemistry. While this line of research has translational relevance for over half the population, neuroscience is notably guilty of female participant exclusion in research studies, with the male brain implicitly treated as the default model and only a minority of basic and clinical neuroscience studies including a female sample (15-18). Female underrepresentation in neuroscience directly limits opportunities for basic scientific discovery; and without basic knowledge of the biological underpinnings of sex differences, we cannot address critical sexdriven differences in pathology. Thus, my doctoral thesis aims to deliberately investigate the influence of sex and ovarian hormones on brain states in health as well as in vulnerability to depression and cognitive impairment:Table of Contents List of Abbreviations ..................................................................................................................... i List of Figures .............................................................................................................................. ii Acknowledgements .....................................................................................................................iii 1 INTRODUCTION .....................................................................................................................1 1.1 Lifespan approach: Sex, hormones, and metabolic risk factors for cognitive health .......3 1.2 Reproductive years: Healthy models of ovarian hormones, serotonin, and the brain ......4 1.2.1 Ovarian hormones and brain structure across the menstrual cycle ........................4 1.2.2 Serotonergic modulation and brain function in oral contraceptive users .................6 1.3 Neuropsychiatric risk models: Reproductive subtypes of depression ...............................8 1.3.1 Hormonal transition states and brain chemistry measured by PET imaging ...........8 1.3.2 Serotonin transporter binding across the menstrual cycle in PMDD patients .......10 2 PUBLICATIONS ....................................................................................................................12 2.1 Publication 1: Association of estradiol and visceral fat with structural brain networks and memory performance in adults .................................................................................13 2.2 Publication 2: Longitudinal 7T MRI reveals volumetric changes in subregions of human medial temporal lobe to sex hormone fluctuations ..............................................28 2.3 Publication 3: One-week escitalopram intake alters the excitation-inhibition balance in the healthy female brain ...............................................................................................51 2.4 Publication 4: Using positron emission tomography to investigate hormone-mediated neurochemical changes across the female lifespan: implications for depression ..........65 2.5 Publication 5: Increase in serotonin transporter binding across the menstrual cycle in patients with premenstrual dysphoric disorder: a case-control longitudinal neuro- receptor ligand PET imaging study ..................................................................................82 3 SUMMARY ...........................................................................................................................100 References ..............................................................................................................................107 Supplementary Publications ...................................................................................................114 Author Contributions to Publication 1 .....................................................................................184 Author Contributions to Publication 2 .....................................................................................186 Author Contributions to Publication 3 .....................................................................................188 Author Contributions to Publication 4 .....................................................................................190 Author Contributions to Publication 5 .....................................................................................191 Declaration of Authenticity ......................................................................................................193 Curriculum Vitae ......................................................................................................................194 List of Publications ................................................................................................................195 List of Talks and Posters ......................................................................................................19

Frontal lobe epilepsy, sleep and parasomnias.

A close relationship exists between sleep and epilepsy. While many forms of epilepsy may be influenced by the sleep-wake cycle, this phenomenon is particularly evident in frontal lobe epilepsy where affected individuals may experience seizures exclusively during sleep (nocturnal frontal lobe epilepsy, NFLE). In this thesis, three aspects of the relationship between sleep and frontal lobe epilepsy are examined. Firstly, serotonergic neurotransmission across the human sleep-wake cycle was studied using the novel PET ligand l8F-MPPF, a serotonergic 5HT)A receptor radioligand sensitive to endogenous serotonin release. Fourteen individuals with narcolepsy underwent 18F-MPPF PET scans during sleep and wakefulness. The study demonstrated a 13% increase in 18F-MPPF binding potential (p<0.01) during sleep, indicating a reduction in serotoninergic neurotransmission, in line with existing animal data. Secondly, the characterisation of benign, non-epileptic parasomnias and their distinction from nocturnal frontal lobe seizures was addressed in two studies. The first comprised an analysis of the historical features of these conditions, and included the development and validation of a clinical scale for the diagnosis of nocturnal events. The second comprised a detailed semiological analysis of a series of parasomnias recorded on video-EEG monitoring, and a statistical comparison with seizures in NFLE. Although similarities between NFLE and parasomnias were observed, the results provide an evidence base for the confident distinction of these disorders. Finally, the familial form of NFLE (autosomal dominant nocturnal frontal lobe epilepsy, ADNFLE) is associated with mutations in genes for nicotinic acetylcholine receptor subunits, but recognised mutations account for only a minority of reported cases. The last study presented here is a clinical and genetic analysis of two large families with an unusually severe ADNFLE phenotype. Affected individuals had refractory epilepsy and increased rates of mental retardation and psychiatric disorders and, in one family, linkage studies suggest a previously unrecognised underlying mechanism

Psychiatric Disorders

A psychiatric disorder is defined as any complex condition that involves the impairment of cognitive, emotional, or behavioral functioning. Aside from knowing the physical organic factors, its causal pathology has remained a mystery. Regarding recent advances in psychiatry and neurosciences, psychiatric disorders have been closely associated with socio-cultural, psychological, biochemical, epigenetic or neural-networking factors. A need for diverse approaches or support strategies is present, which should serve as common knowledge, empathetic views or useful skills for specialists in the filed. This book contains multifarious and powerful papers from all over the world, addressing themes such as the neurosciences, psychosocial interventions, medical factors, possible vulnerability and traumatic events. Doubtlessly, this book will be fruitful for future development and collaboration in "world psychiatry"

Segmentation of neuroanatomy in magnetic resonance images

Segmentation in neurological Magnetic Resonance Imaging (MRI) is necessary for volume measurement, feature extraction and for the three-dimensional display of neuroanatomy. This thesis proposes several automated and semi-automated methods which offer considerable advantages over manual methods because of their lack of subjectivity, their data reduction capabilities, and the time savings they give. Work has concentrated on the use of dual echo multi-slice spin-echo data sets in order to take advantage of the intrinsically multi-parametric nature of MRI. Such data is widely acquired clinically and segmentation therefore does not require additional scans. The literature has been reviewed. Factors affecting image non-uniformity for a modem 1.5 Tesla imager have been investigated. These investigations demonstrate that a robust, fast, automatic three-dimensional non-uniformity correction may be applied to data as a pre-processing step. The merit of using an anisotropic smoothing method for noisy data has been demonstrated. Several approaches to neurological MRI segmentation have been developed. Edge-based processing is used to identify the skin (the major outer contour) and the eyes. Edge-focusing, two threshold based techniques and a fast radial CSF identification approach are proposed to identify the intracranial region contour in each slice of the data set. Once isolated, the intracranial region is further processed to identify CSF, and, depending upon the MRI pulse sequence used, the brain itself may be sub-divided into grey matter and white matter using semiautomatic contrast enhancement and clustering methods. The segmentation of Multiple Sclerosis (MS) plaques has also been considered. The utility of the stack, a data driven multi-resolution approach to segmentation, has been investigated, and several improvements to the method suggested. The factors affecting the intrinsic accuracy of neurological volume measurement in MRI have been studied and their magnitudes determined for spin-echo imaging. Geometric distortion - both object dependent and object independent - has been considered, as well as slice warp, slice profile, slice position and the partial volume effect. Finally, the accuracy of the approaches to segmentation developed in this thesis have been evaluated. Intracranial volume measurements are within 5% of expert observers' measurements, white matter volumes within 10%, and CSF volumes consistently lower than the expert observers' measurements due to the observers' inability to take the partial volume effect into account