Neuropathogenesis in glutaric aciduria type I and methylmalonic aciduria

Glutaric aciduria type-I (GA-I) and methylmalonic aciduria (MMA-uria) are two neurometabolic diseases manifesting in neonatal period and early childhood. They belong to the group of organic acidurias and are caused by defects in the catabolism of amino acids, leading to massive accumulation of toxic metabolites in the body and severe brain injury. Therapeutic strategies are mainly based on reversing catabolic state during metabolic crisis and dietary protein restriction that both aim to prevent extra production of toxic metabolites. Specific and neuroprotective treatments are missing because the mechanisms of brain damage in these diseases are only poorly understood. The principal objective of my work was to develop in vitro models for both diseases aiming at elucidation of toxic effects of the main metabolites accumulating in GA-I (glutaric acid (GA) and 3-hydroxy glutaric acid (3-OHGA)) and MMA-uria (methylmalonic acid (MMA), propionic acid (PA) and 2-methylcitric acid (2-MCA)) on developing brain cells, and to study the cellular pathways targeted by these deleterious effects in order to find new therapeutic potentials. We used re-aggregated embryonic rat brain cells in organotypic 3D cultures, which were exposed to toxic metabolites at different developing stages of the cultures. In parallel, we studied the cellular localization of the defected enzyme in GA-I, glutaryl-CoA dehydrogenase (GCDH), in the brain and peripheral tissues of rats in adulthood and during embryonic development. GCDH expression: GCDH showed a strong neuronal expression in embryonic central and peripheral nervous system. In the adult brain, GCDH expression was exclusively neuronal with the strongest signal in cerebral cortex and Purkinje cells. GCDH expression was homogenous in embryonic peripheral organs with high levels in intestinal mucosa at late stages. Strong GCDH expression was also observed in liver and intestinal mucosa and with lower intensity in muscles, convoluted renal tubules and renal collecting tubes in adult peripheral organs. GA-I and MMA-uria in vitro models: 3-OHGA (for GA-I) and 2-MCA (for MMA-uria) showed the most deleterious effects at early stages of the cultures with morphological and biochemical alterations and induction of cell death. 3-OHGA and 2-MCA caused astrocytic cell suffering reflected by astrocytic fiber loss and swelling and retardation in oligodendrocytic maturation and/or differentiation. High ammonium increase concomitant with glutamine decrease was observed in these cultures. Neurons were not substantially affected. Our studies revealed that brain-cell generated ammonia may play a role in the neuropathogenesis of these diseases. Thus, developing neuroprotective strategies that target ammonium toxicity in the brain of GA-I and MMA-uria patients might be important according to our findings. -- L'acidurie glutarique de type I (GA-I) et l'acidurie méthylmalonique (MMA-urie) sont deux maladies neurométaboliques se manifestant durant la période néonatale ou la petite enfance, et qui appartiennent aux aciduries organiques. Elles sont causées par des défauts dans le catabolisme des acides aminés, conduisant à une accumulation des métabolites toxiques dans le corps et aussi des lésions cérébrales sévères. Le traitement est limité à une prise en charge d'urgence pendant la crise métabolique et à une diète restreinte en protéines naturelles. Des traitements spécifiques, neuroprotecteurs manquent principalement parce que les mécanismes conduisant aux lésions cérébrales dans ces maladies sont peu connus. L'objectif principal de mon travail était d'élucider les effets toxiques des métabolites accumulés dans GA-I (l'acide glutarique (GA) et l'acide 3-hydroxyglutarique (3-OHGA)) et MMA-uria (l'acide méthylmalonique (MMA), l'acide propionique (PA) et l'acide 2-méthylcitrique(2-MCA) sur les cellules du cerveau ainsi que les voies cellulaires impliquées, dans le but de trouver de potentielles nouvelles stratégies thérapeutiques. Nous avons utilisé un modèle in vitro de cultures 3D de cellules de cerveau d'embryons de rat (en développement) en les exposant aux métabolites toxiques à différents stades de développement des cultures. En parallèle, nous avons étudié la localisation cellulaire de l'enzyme déficiente dans GA-I, la CoA-glutarly déshydrogénase (GCDH), dans le cerveau et les organes périphériques des rats adultes et pendant le développement embryonnaire. L'expression de GCDH: GCDH a montré une expression neuronale forte dans le système nerveux chez l'embryon et le cerveau adulte. L'expression était homogène dans les organes périphériques avec une forte expression dans l'intestin. Les modèles in vitro de GA-I et MMA-uria : 3-OHGA en modèle GA-I et 2-MCA en modèle MMA-uria ont montré les effets délétères les plus importants avec des altérations morphologiques des cellules et biochimiques dans le milieu de culture et l'induction de mort cellulaire non-apoptotique (3-OHGA) ou apoptotique (2-MCA). 3-OHGA et 2-MCA ont provoqué une souffrance astrocytaire avec perte des fibres et gonflement et un retard de maturation et/ou de différentiation des oligodendrocytes. Une augmentation importante d'ammonium avec une diminution concomitante de glutamine a été observée dans les cultures. Les neurones n'étaient pas vraiment affectés. Nos études ont révélé que l'ammonium généré par les cellules cérébrales pourrait jouer un rôle dans la neuropathogenèse de ces deux maladies. Par conséquent, développer des stratégies neuroprotectrices ciblant la toxicité de l'ammonium dans le cerveau des patients atteints de GA-I ou MMA-urie pourrait être très important selon nos résultats.

European Stroke Organisation (ESO) guidelines for the management of temperature in patients with acute ischemic stroke.

BACKGROUND: Hyperthermia is a frequent complication in patients with acute ischemic stroke. On the other hand, therapeutically induced hypothermia has shown promising potential in animal models of focal cerebral ischemia. This Guideline Document presents the European Stroke Organisation guidelines for the management of temperature in patients with acute ischemic stroke. METHODS: A multidisciplinary group identified related questions and developed its recommendations based on evidence from randomized controlled trials elaborating the Grading of Recommendations Assessment, Development, and Evaluation approach. This Guideline Document was reviewed within the European Stroke Organisation and externally and was approved by the European Stroke Organisation Guidelines Committee and the European Stroke Organisation Executive Committee. RESULTS: We found low-quality evidence, and therefore, we cannot make any recommendation for treating hyperthermia as a means to improve functional outcome and/or survival in patients with acute ischemic stroke and hyperthermia; moderate evidence to suggest against routine prevention of hyperthermia with antipyretics as a means to improve functional outcome and/or survival in patients with acute ischemic stroke and normothermia; very low-quality evidence to suggest against routine induction of hypothermia as a means to improve functional outcome and/or survival in patients with acute ischemic stroke. CONCLUSIONS: The currently available data about the management of temperature in patients with acute ischemic stroke are limited, and the strengths of the recommendations are therefore weak. We call for new randomized controlled trials as well as recruitment of eligible patients to ongoing randomized controlled trials to allow for better-informed recommendations in the future.

Interleukin-22 is increased in multiple sclerosis patients and targets astrocytes.

BACKGROUND: Increasing evidences link T helper 17 (Th17) cells with multiple sclerosis (MS). In this context, interleukin-22 (IL-22), a Th17-linked cytokine, has been implicated in blood brain barrier breakdown and lymphocyte infiltration. Furthermore, polymorphism between MS patients and controls has been recently described in the gene coding for IL-22 binding protein (IL-22BP). Here, we aimed to better characterize IL-22 in the context of MS. METHODS: IL-22 and IL-22BP expressions were assessed by ELISA and qPCR in the following compartments of MS patients and control subjects: (1) the serum, (2) the cerebrospinal fluid, and (3) immune cells of peripheral blood. Identification of the IL-22 receptor subunit, IL-22R1, was performed by immunohistochemistry and immunofluorescence in human brain tissues and human primary astrocytes. The role of IL-22 on human primary astrocytes was evaluated using 7-AAD and annexin V, markers of cell viability and apoptosis, respectively. RESULTS: In a cohort of 141 MS patients and healthy control (HC) subjects, we found that serum levels of IL-22 were significantly higher in relapsing MS patients than in HC but also remitting and progressive MS patients. Monocytes and monocyte-derived dendritic cells contained an enhanced expression of mRNA coding for IL-22BP as compared to HC. Using immunohistochemistry and confocal microscopy, we found that IL-22 and its receptor were detected on astrocytes of brain tissues from both control subjects and MS patients, although in the latter, the expression was higher around blood vessels and in MS plaques. Cytometry-based functional assays revealed that addition of IL-22 improved the survival of human primary astrocytes. Furthermore, tumor necrosis factor α-treated astrocytes had a better long-term survival capacity upon IL-22 co-treatment. This protective effect of IL-22 seemed to be conferred, at least partially, by a decreased apoptosis. CONCLUSIONS: We show that (1) there is a dysregulation in the expression of IL-22 and its antagonist, IL-22BP, in MS patients, (2) IL-22 targets specifically astrocytes in the human brain, and (3) this cytokine confers an increased survival of the latter cells.

The 16p11.2 rearrangments genetic paradigms for obesity and neurodevelopmental disorders.

Recent discoveries of recurrent and reciprocal Copy Number Variants (CNVs) using genome- wide studies have led to a new understanding of the etiology of neuropsychiatric disorders. CNVs represent loss (deletion) or gain (duplication) of genomic material. This thesis work is focused on CNVs at the 16p11.2 BP4-BP5 locus, which are among the most frequent etiologies of neurodevelopmental disorders and have been associated with Autism Spectrum Disorders (ASD), schizophrenia, cognitive impairment, alterations of brain size as well as obesity and underweight. Because deletion and duplication of the 16p11.2 locus occur frequently and recurrently (with the same breakpoints), CNVs at this locus represent a powerful paradigm to understand how a genomic region may modulate cognitive and behavioral traits as well as the relationship and shared mechanisms between distinct psychiatric diagnoses such as ASD and schizophrenia. The present dissertation includes three studies: 1) The first project aims at identifying structural brain-imaging endophenotypes in 16p11.2 CNVs carriers at risk for ASD and schizophrenia. The results show that gene dosage at the 16p11.2 locus modulates global brain volumes and neural circuitry, including the reward system, language and social cognition circuits. 2) The second investigates the neuropsychological profile in 16p11.2 deletion and duplication carriers. While deletion carriers show specific deficits in language and inhibition, the profile of duplication carriers is devoid of specific weaknesses and presents enhanced performance in a verbal memory task. 3) The third study on food-related behaviors in 16p11.2 deletion and duplication carriers shows that alterations of the reponse to satiety are present in CNV carriers before the onset of obesity, pointing toward a potential mechanism driving the Body Mass Index increase in deletion carriers. Dysfunctions in the reward system and dopaminergic circuitries could represent a common mechanism playing a role in the phenotype and could be investigated in future studies. Our data strongly suggest that complex cognitive traits correlate to gene dosage in humans. Larger studies including expression data would allow elucidating the contribution of specific genes to these different gene dosage effects. In conclusion, a systematic and careful investigation of cognitive, behavioral and intermediate phenotypes using a gene dosage paradigm has allowed us to advance our understanding of the 16p11.2 BP4-BP5 locus and its effects on neurodevelopment. -- La récente découverte de variations du nombre de copies (CNVs pour 'copy number variants') dans le génome humain a amélioré nos connaissances sur l'étiologie des troubles neuropsychiatriques. Un CNV représente une perte (délétion) ou un gain (duplication) de matériel génétique sur un segment chromosomique. Ce travail de thèse est focalisé sur les CNVs réciproques (délétion et duplication) dans la région 16p11.2 BP4-BP5. Ces CNVs sont une cause fréquente de troubles neurodéveloppementaux et ont été associés à des phénotypes « en miroir » tels que obésité/sous-poids ou macro/microcéphalie mais aussi aux troubles du spectre autistique (TSA), à la schizophrénie et au retard de développement/déficience intellectuelle. La fréquence et la récurrence de la délétion et de la duplication aux mêmes points de cassure font de ces CNVs un paradigme unique pour étudier la relation entre dosage génique et les traits cognitifs et comportementaux, ainsi que les mécanismes partagés par des troubles psychiatriques apparemment distincts tels que les TSA et la schizophrénie. Ce travail de thèse comporte trois études distinctes : 1) l'étude en neuroimagerie structurelle identifie les endophénotypes chez les porteurs de la délétion ou de la duplication. Les résultats montrent une influence du dosage génique sur le volume cérébral total et certaines structures dans les systèmes de récompense, du langage et de la cognition sociale. 2) L'étude des profils neuropsychologiques chez les porteurs de la délétion ou de la duplication montre que la délétion est associée à des troubles spécifiques du langage et de l'inhibition alors que les porteurs de la duplication ne montrent pas de faiblesse spécifique mais des performances mnésiques verbales supérieures à leur niveau cognitif global. 3) L'étude sur les comportements alimentaires met en évidence une altération de la réponse à la satiété qui est présente avant l'apparition de l'obésité. Un dysfonctionnement dans le système de récompense et les circuits dopaminergiques pourrait représenter un mécanisme commun aux différents phénotypes observés chez ces individus porteurs de CNVs au locus 16p11.2. En conclusion, l'utilisation du dosage génique comme outil d'investigation des phénotypes cliniques et endophénotypes nous a permis de mieux comprendre le rôle de la région 16p11.2 BP4-BP5 dans le neurodéveloppement.

Neuronal death after perinatal cerebral hypoxia-ischemia: Focus on autophagy-mediated cell death.

Neonatal hypoxic-ischemic encephalopathy is a critical cerebral event occurring around birth with high mortality and neurological morbidity associated with long-term invalidating sequelae. In view of the great clinical importance of this condition and the lack of very efficacious neuroprotective strategies, it is urgent to better understand the different cell death mechanisms involved with the ultimate aim of developing new therapeutic approaches. The morphological features of three different cell death types can be observed in models of perinatal cerebral hypoxia-ischemia: necrotic, apoptotic and autophagic cell death. They may be combined in the same dying neuron. In the present review, we discuss the different cell death mechanisms involved in neonatal cerebral hypoxia-ischemia with a special focus on how autophagy may be involved in neuronal death, based: (1) on experimental models of perinatal hypoxia-ischemia and stroke, and (2) on the brains of human neonates who suffered from neonatal hypoxia-ischemia.

In Vivo Longitudinal (1)H MRS Study of Transgenic Mouse Models of Prion Disease in the Hippocampus and Cerebellum at 14.1 T.

In vivo (1)H MR spectroscopy allows the non invasive characterization of brain metabolites and it has been used for studying brain metabolic changes in a wide range of neurodegenerative diseases. The prion diseases form a group of fatal neurodegenerative diseases, also described as transmissible spongiform encephalopathies. The mechanism by which prions elicit brain damage remains unclear and therefore different transgenic mouse models of prion disease were created. We performed an in vivo longitudinal (1)H MR spectroscopy study at 14.1 T with the aim to measure the neurochemical profile of Prnp -/- and PrPΔ32-121 mice in the hippocampus and cerebellum. Using high-field MR spectroscopy we were able to analyze in details the in vivo brain metabolites in Prnp -/- and PrPΔ32-121 mice. An increase of myo-inositol, glutamate and lactate concentrations with a decrease of N-acetylaspartate concentrations were observed providing additional information to the previous measurements.

Visual performance in preterm infants with brain injuries compared with low-risk preterm infants

Background: Neonatal brain injuries are the main cause of visual deficit produced by damage to posterior visual pathways.While there are several studies of visual function in low-risk preterm infants or older children with brain injuries, research in children of early age is lacking. Aim: To assess several aspects of visual function in preterm infants with brain injuries and to compare them with another group of low-risk preterm infants of the same age. Study design and subjects: Forty-eight preterm infants with brain injuries and 56 low-risk preterm infants. Outcome measures: The ML Leonhardt Battery of Optotypes was used to assess visual functions. This test was previously validated at a post-menstrual age of 40 weeks in newborns and at 30-plus weeks in preterm infants. Results: The group of preterminfants with brain lesions showed a delayed pattern of visual functions in alertness, fixation, visual attention and tracking behavior compared to infants in the healthy preterm group. The differences between both groups, in the visual behaviors analyzed were around 30%. These visual functions could be identified from the first weeks of life. Conclusion: Our results confirm the importance of using a straightforward screening test with preterminfants in order to assess altered visual function, especially in infants with brain injuries. The findings also highlight the need to provide visual stimulation very early on in life.

Neural synchrony indexes impaired motor slowing after errors and novelty following white matter damage.

In humans, action errors and perceptual novelty elicit activity in a shared frontostriatal brain network, allowing them to adapt their ongoing behavior to such unexpected action outcomes. Healthy and pathologic aging reduces the integrity of white matter pathways that connect individual hubs of such networks and can impair the associated cognitive functions. Here, we investigated whether structural disconnection within this network because of small-vessel disease impairs the neural processes that subserve motor slowing after errors and novelty (post-error slowing, PES; post-novel slowing, PNS). Participants with intact frontostriatal circuitry showed increased right-lateralized beta-band (12-24 Hz) synchrony between frontocentral and frontolateral electrode sites in the electroencephalogram after errors and novelty, indexing increased neural communication. Importantly, this synchrony correlated with PES and PNS across participants. Furthermore, such synchrony was reduced in participants with frontostriatal white matter damage, in line with reduced PES and PNS. The results demonstrate that behavioral change after errors and novelty result from coordinated neural activity across a frontostriatal brain network and that such cognitive control is impaired by reduced white matter integrity.

Cytokine-induced sleep: Neurons respond to TNF with production of chemokines and increased expression of Homer1a in vitro.

Interactions of neurons with microglia may play a dominant role in sleep regulation. TNF may exert its somnogeneic effects by promoting attraction of microglia and their processes to the vicinity of dendrites and synapses. We found TNF to stimulate neurons (i) to produce CCL2, CCL7 and CXCL10, chemokines acting on mononuclear phagocytes and (ii) to stimulate the expression of the macrophage colony stimulating factor (M-CSF/Csf1), which leads to elongation of microglia processes. TNF may also act on neurons by affecting the expression of genes essential in sleep-wake behavior. The neuronal expression of Homer1a mRNA, increases during spontaneous and enforced periods of wakefulness. Mice with a deletion of Homer1a show a reduced wakefulness with increased non-rapid eye movement (NREM) sleep during the dark period. Recently the TNF-dependent increase of NREM sleep in the dark period of mice with CD40-induced immune activation was found to be associated with decreased expression of Homer1a. In the present study we investigated the effects of TNF and IL-1β on gene expression in cultures of the neuronal cell line HT22 and cortical neurons. TNF slightly increased the expression of Homer1a and IL-1β profoundly enhanced the expression of Early growth response 2 (Egr2). The data presented here indicate that the decreased expression of Homer1a, which was found in the dark period of mice with CD40-induced increase of NREM sleep is not due to inhibitory effects of TNF and IL-1β on the expression of Homer1a in neurons.

Brain metastasis as initial presentation of papillary adenocarcinoma of the lung: case report

The authors describe the case of a 33-year-old patient with history of seizures alone without any previous symptom, being diagnosed with brain metastases from primary papillary adenocarcinoma of the lung. Emphasis is given to the diagnostic investigation for brain metastasis and prognostic evaluation of papillary adenocarcinoma of the lung, and a brief literature review on such diseases is performed.

Brain imaging studies in severe somatization

Somatization was described 4000 years ago but the pathophysiology of the, phenomenon is unknown. The aim of this investigation was to explore whether central nervous system (CNS) pathology is associated with severe somatization which was operationalized as somatization disorder (SD) and undifferentiated somatoform disorder. The study sample consisted of severely somatizing people who were included into the study after a multi-phase screening procedure in order to exclude psychiatric comorbidities and physical illnesses. Diagnosis of somatization disorder or undifferentiated sofatoform disorder were set according to Diagnostic and Statistical Manual of Mental Disorders 4th ed. (DSM-IV). The first study explored the regional cerebral metabolic rate of glucose (rCMRGlc) in severely somatizing females and found it to be reduced in several regions of the brain compared to healthy controls. The second study observed brain morphology with magnetic resonance imaging (MRI) based on the findings from the first study and showed enlarged caudate nuclei in somatizing women compared to healthy volunteers. The third study investigated temperament factors and brain metabolism, and their association with severe somatization. Low caudate and putamen metabolism, low novelty seeking as well as high harm avoidance were found to be associated with severe somatization in women, reduced caudate metabolism having the strongest association. The last study is a report of man with left-side gradient of multiple symptoms of unknown origin in the body. The examination revealed a hypermetabolic nucleus putamen on the contralateral side. All the main results reported in these four articles are original findings. The results suggest that CNS pathology is involved in the pathophysiology of severe somatization.

Theta EEG oscillatory activity and auditory change detection

The mismatch negativity is an electrophysiological marker of auditory change detection in the event-related brain potential and has been proposed to reflect an automatic comparison process between an incoming stimulus and the representation of prior items in a sequence. There is evidence for two main functional subcomponents comprising the MMN, generated by temporal and frontal brain areas, respectively. Using data obtained in an MMN paradigm, we performed time-frequency analysis to reveal the changes in oscillatory neural activity in the theta band. The results suggest that the frontal component of the MMN is brought about by an increase in theta power for the deviant trials and, possibly, by an additional contribution of theta phase alignment. By contrast, the temporal component of the MMN, best seen in recordings from mastoid electrodes, is generated by phase resetting of theta rhythm with no concomitant power modulation. Thus, frontal and temporal MMN components do not only differ with regard to their functional significance but also appear to be generated by distinct neurophysiological mechanisms.

Synthesis and biological activity of sulfur compounds showing structural analogy with combretastatin A-4

We extended our previous exploration of sulfur bridges as bioisosteric replacements for atoms forming the bridge between the aromatic rings of combretastatin A-4. Employing coupling reactions between 5-iodo-1,2,3-trimethoxybenzene and substituted thiols, followed by oxidation to sulfones with m-CPBA, different locations for attaching the sulfur atom to ring A through the synthesis of nine compounds were examined. Antitubulin activity was performed with electrophoretically homogenous bovine brain tubulin, and activity occurred with the 1,2,3-trimethoxy-4-[(4-methoxyphenyl)thio]benzene (12), while the other compounds were inactive. The compounds were also tested for leishmanicidal activity using promastigote forms of Leishmania braziliensis (MHOM/BR175/M2904), and the greatest activity was observed with 1,2,3-trimethoxy-4-(phenylthio)benzene (10) and 1,2,3-trimethoxy-4-[(4-methoxyphenyl) sulfinyl]benzene (15).

Generation and Characterization of Knockout Mice and Analysis of Patient Material Demonstrates a Role for Tissue Inhibitor of Metalloproteinases 4 (Timp4) in the Cardiovascular System and Tumor Metastasis

This thesis focuses on tissue inhibitor of metalloproteinases 4 (TIMP4) which is the newest member of a small gene and protein family of four closely related endogenous inhibitors of extracellular matrix (ECM) degrading enzymes. Existing data on TIMP4 suggested that it exhibits a more restricted expression pattern than the other TIMPs with high expression levels in heart, brain, ovary and skeletal muscle. These observations and the fact that the ECM is of special importance to provide the cardiovascular system with structural strength combined with elasticity and distensibility, prompted the present molecular biologic investigation on TIMP4. In the first part of the study the murine Timp4 gene was cloned and characterized in detail. The structure of murine Timp4 genomic locus resembles that in other species and of the other Timps. The highest Timp4 expression was detected in heart, ovary and brain. As the expression pattern of Timp4 gives only limited information about its role in physiology and pathology, Timp4 knockout mice were generated next. The analysis of Timp4 knockout mice revealed that Timp4 deficiency has no obvious effect on the development, growth or fertility of mice. Therefore, Timp4 deficient mice were challenged using available cardiovascular models, i.e. experimental cardiac pressure overload and myocardial infarction. In the former model, Timp4 deficiency was found to be compensated by Timp2 overexpression, whereas in the myocardial infarct model, Timp4 deficiency resulted in increased mortality due to increased susceptibility for cardiac rupture. In the wound healing model, Timp4 deficiency was shown to result in transient retardation of re-epithelialization of cutaneous wounds. Melanoma tumor growth was similar in Timp4 deficient and control mice. Despite of this, lung metastasis of melanoma cells was significantly increased in Timp4 null mice. In an attempt to translate the current findings to patient material, TIMP4 expression was studied in human specimens representing different inflammatory cardiovascular pathologies, i.e. giant cell arteritis, atherosclerotic coronary arteries and heart allografts exhibiting signs of chronic rejection. The results showed that cardiovascular expression of TIMP4 is elevated particularly in areas exhibiting inflammation. The results of the present studies suggest that TIMP4 has a special role in the regulation of tissue repair processes in the heart, and also in healing wounds and metastases. Furthermore, evidence is provided suggesting the usefulness of TIMP4 as a novel systemic marker for vascular inflammation.

Design and characterization of large area position sensitive radiation detectors

Planar, large area, position sensitive silicon detectors are widely utilized in high energy physics research and in medical, computed tomography (CT). This thesis describes author's research work relating to development of such detector components. The key motivation and objective for the research work has been the development of novel, position sensitive detectors improving the performance of the instruments they are intended for. Silicon strip detectors are the key components of barrel-shaped tracking instruments which are typically the innermost structures of high energy physics experimental stations. Particle colliders such as the former LEP collider or present LHC produce particle collisions and the silicon strip detector based trackers locate the trajectories of particles emanating from such collisions. Medical CT has become a regular part of everyday medical care in all developed countries. CT scanning enables x-ray imaging of all parts of the human body with an outstanding structural resolution and contrast. Brain, chest and abdomen slice images with a resolution of 0.5 mm are possible and latest CT machines are able to image whole human heart between heart beats. The two application areas are presented shortly and the radiation detection properties of planar silicon detectors are discussed. Fabrication methods and preamplifier electronics of the planar detectors are presented. Designs of the developed, large area silicon detectors are presented and measurement results of the key operating parameters are discussed. Static and dynamic performance of the developed silicon strip detectors are shown to be very satisfactory for experimental physics applications. Results relating to the developed, novel CT detector chips are found to be very promising for further development and all key performance goals are met.