<p>Mild Cognitive Impairment (MCI) refers to a transitional stage between normal aging and dementia. The purpose of this study was to predict the development of MCI patients based on cognitive function. 222 MCI patients were studied at baseline and at a follow-up of 2 years. Using discriminant analysis, they were predicted into four diagnostic groups: Improved, Stable MCI, Dementia of the Alzheimer’s Type (AD) and Other Dementia. Using four tests - Rey-Osterrieth Complex Figure Test recall, Auditory-Verbal Learning Test recall, TMTB time and Digit Symbol – overall 62.6% of cases were correctly classified after cross-validation. The rate of prediction in this study was 1.8 times better than chance, which is better than reported in most other studies. The model did best for the AD group with 80% of cases correctly classified. However, most cases in the Other Dementia group were also classified as AD.</p>

<p>Background and objectives</p><p>Stress is in several studies mentioned as the most frequent trigger of headache. Nevertheless, the exact mechanisms by which stress induces headache is poorly understood and relatively few studies with rigorous scientific methods mimicking real life settings have been performed. In the present study an experimental model was used to study muscular, cardiovascular and biochemical responses to cognitive low-grade stress and investigate relationships between these responses and pain in the head and shoulder/neck areas.</p><p>Methods</p><p>This thesis is based on data recorded during and after a stress test in healthy controls and patients with migraine or tension-type headache (TTH). The stress test consisted of a two-choice reaction time test designed to imitate real-life working conditions in a stressful office environment. The stress test lasted for 60 minutes and was followed by 30 minutes of relaxation. We recorded pain and surface electromyographic (EMG) activity in the trapezius, splenius, temporalis and frontalis muscles, in addition to blood pressure (BP), heart rate (HR), skin blood flow (BF) in the fingers as well as noradrenaline, adrenaline and cortisol levels in blood sampled before and after the stress test.</p><p>Results</p><p>The main findings were higher pain responses in the temporalis and frontalis areas (with similar trends for trapezius and splenius) and more potentiation of pain during the test when comparing TTH patients with controls. Migraine patients developed more pain in the splenius and temporalis areas than controls. TTH patients had a more generalised pain increase in all areas, while pain increase was more regional (more pain in the neck/shoulder compared to the head) in migraine. TTH patients had delayed pain recovery in all areas compared to controls, while migraine had delayed pain recovery in the trapezius and temporalis areas. The temporalis EMG response was increased in migraineurs compared to controls, but there were no other differences in EMG responses between the diagnostic groups, and EMG responses were not correlated with pain responses. TTH patients had delayed EMG recovery in the trapezius compared to controls and migraineurs.</p><p>Cardiovascular responses to cognitive stress in migraine patients did not differ from those in control subjects. In TTH patients, a lack of HR-adaptation during stress was found and a trend towards a delayed systolic BP response during stress was also observed. Finger BF recovery was delayed after stress and stress-induced pain was associated with less vasoconstriction in TTH during recovery.</p><p>TTH patients had significantly less cortisol change to stress than controls and migraineurs, which has to our knowledge not been reported before. Migraineurs had lower noradrenaline levels in blood platelets compared to controls, and pain responses correlated negatively with noradrenaline levels in migraineurs.</p><p>Conclusions</p><p>Our results suggest that both patients with migraine and TTH respond differently to stress compared to controls. The increased pain responses and potentiation of pain observed in TTH support the hypothesis that central sensitization is important in these patients, and together with EMG recovery data suggest that TTH patients may be sensitized both in nociceptive and somatomotor neural pathways. Data on migraineurs points towards more limited regional pain sensitization and suggests that neck pain may be a trigger or prodrome to stress-induced migraine attacks in some patients. Surfacedetectable muscular activity during stress did not appear to be causal for pain in migraine or TTH patients.</p><p>Based on pain, cardiovascular and cortisol data we hypothesize that TTH patients may have different stress adaptive mechanisms than controls and migraineurs, involving regulation of the cardiovascular system, the hypothalamus-pituitary-adrenocortical axis and pain control systems.</p><p>For migraineurs, the lower noradrenaline levels and the inverse correlation found between noradrenaline and pain responses suggests that the sympathoneural response to stress appears to be closely linked with stress-induced pain in these patients.</p>

Background and objectives Stress is in several studies mentioned as the most frequent trigger of headache. Nevertheless, the exact mechanisms by which stress induces headache is poorly understood and relatively few studies with rigorous scientific methods mimicking real life settings have been performed. In the present study an experimental model was used to study muscular, cardiovascular and biochemical responses to cognitive low-grade stress and investigate relationships between these responses and pain in the head and shoulder/neck areas. Methods This thesis is based on data recorded during and after a stress test in healthy controls and patients with migraine or tension-type headache (TTH). The stress test consisted of a two-choice reaction time test designed to imitate real-life working conditions in a stressful office environment. The stress test lasted for 60 minutes and was followed by 30 minutes of relaxation. We recorded pain and surface electromyographic (EMG) activity in the trapezius, splenius, temporalis and frontalis muscles, in addition to blood pressure (BP), heart rate (HR), skin blood flow (BF) in the fingers as well as noradrenaline, adrenaline and cortisol levels in blood sampled before and after the stress test. Results The main findings were higher pain responses in the temporalis and frontalis areas (with similar trends for trapezius and splenius) and more potentiation of pain during the test when comparing TTH patients with controls. Migraine patients developed more pain in the splenius and temporalis areas than controls. TTH patients had a more generalised pain increase in all areas, while pain increase was more regional (more pain in the neck/shoulder compared to the head) in migraine. TTH patients had delayed pain recovery in all areas compared to controls, while migraine had delayed pain recovery in the trapezius and temporalis areas. The temporalis EMG response was increased in migraineurs compared to controls, but there were no other differences in EMG responses between the diagnostic groups, and EMG responses were not correlated with pain responses. TTH patients had delayed EMG recovery in the trapezius compared to controls and migraineurs. Cardiovascular responses to cognitive stress in migraine patients did not differ from those in control subjects. In TTH patients, a lack of HR-adaptation during stress was found and a trend towards a delayed systolic BP response during stress was also observed. Finger BF recovery was delayed after stress and stress-induced pain was associated with less vasoconstriction in TTH during recovery. TTH patients had significantly less cortisol change to stress than controls and migraineurs, which has to our knowledge not been reported before. Migraineurs had lower noradrenaline levels in blood platelets compared to controls, and pain responses correlated negatively with noradrenaline levels in migraineurs. Conclusions Our results suggest that both patients with migraine and TTH respond differently to stress compared to controls. The increased pain responses and potentiation of pain observed in TTH support the hypothesis that central sensitization is important in these patients, and together with EMG recovery data suggest that TTH patients may be sensitized both in nociceptive and somatomotor neural pathways. Data on migraineurs points towards more limited regional pain sensitization and suggests that neck pain may be a trigger or prodrome to stress-induced migraine attacks in some patients. Surfacedetectable muscular activity during stress did not appear to be causal for pain in migraine or TTH patients. Based on pain, cardiovascular and cortisol data we hypothesize that TTH patients may have different stress adaptive mechanisms than controls and migraineurs, involving regulation of the cardiovascular system, the hypothalamus-pituitary-adrenocortical axis and pain control systems. For migraineurs, the lower noradrenaline levels and the inverse correlation found between noradrenaline and pain responses suggests that the sympathoneural response to stress appears to be closely linked with stress-induced pain in these patients.

<p>Neurotrophic factors and their receptors are crucial for the formation of neuronal connections and for the neuronal survival during embryonic development of the nervous system. This has particularly been shown by studies of the PNS. The work of this thesis has aimed at clarifying where and when in the developing retina and its tectal target (as parts of the CNS), certain neurotrophic factors come into play. In a functional perspective, the focus has been on the possible involvement of these factors in the regulation of cell death / survival. Therefore, naturally occuring cell death in the developing avian retina was first studied. From the results, it is concluded that there is an early and a late phase of cell death in the developing retina. The cells dying during the early phase are proliferating retinal precursor cells, and the cells dying later are in the process of terminal differentiation. The timing and distribution of the dying cells suggest that the cell death is regulated. During retinal development two retinal cell types, amacrine cells and horizontal cells, express TrkA, a receptor for the neurotrophin nerve growth factor (NGF). These amacrine cells are shown to undergo cell death during the late cell death phase, but can be rescued by exogenous NGF. The horizontal cells in turn, are supported by NGF in an autocrine manner, and therefore survive. Two other neurotrophic factors brain-derived neurotrophic factor (BDNF) and glial cell-line derived neurotrophic factor (GDNF) are both expressed in the retina and in the target for retinal ganglion cells, the optic tectum. By the results, it is concluded that neuronal activity can regulate the expression of BDNF in the retina and optic tectum. Furthermore, GDNF can stimulate neurite outgrowth from retinal explants of a certain age. Taken together, the main result of this thesis is that neurotrophic factors indeed can work as autocrine survival factors in the developing CNS. </p>

<p>Members of the transforming growth factor-β (TGF-β) superfamily exhibit a range of effects on a host of different cell types. They signal through heteromeric complexes of serine/threonine kinase receptors of type I and type II. Gene targeted mutations of both factors and receptors have revealed that many of them are involved in early embryonic development. This thesis examines the receptors for this superfamily in the nervous system, especially bone morphogenetic protein receptor type II (BMPR-II). It was cloned from chicken nervous tissue, and its and other receptors’ expression in peripheral ganglia, spinal cord and brain of chicken, rat and mouse were examined. BMPR-II, ActR-II and ActR-IA were abundantly expressed throughout development in the nervous system, however with temporal regulation. One ligand of BMPR-II, BMP-7, was found to act synergistically with NT-3 and GDNF on subsets of peripheral neurons to promote survival and neurite outgrowth. A knock-in mouse was generated, encoding a truncated form of BMPR-II coupled to the endogenous tyrosine hydroxylase (TH) gene with an internal ribosome entry site (IRES). For ES-cell selection, a neomycin resistance gene was incorporated into the construct. Homozygous mice carrying the knock-in allele exhibited a small, hypokinetic phenotype. Levels of dopamine, noradrenaline and serotonin were measured, and the catecholamines were found to be lowered, dopamine as much as 97% in the caudate nucleus. The low catecholamine levels may not be an effect of the truncated BMPR-II, but rather a consequence of the knock-in construct reducing TH transcriptional rate. The TH hypomorphic mouse strain generated could find use as a model for catecholamine impaired systems, as seen in Parkinson’s disease.</p>

<p>Stress incontinence and overactive bladder are disorders with a common symptom, urinary incontinence, which is a serious medical and social handicap. Several neurotransmitters regulate the function of the lower urinary tract, including noradrenaline, acetylcholine, and serotonin.</p><p>The present study is part of the search for pharmacological incontinence drugs. The aims of this thesis were to improve the existing pharmacological treatments of urinary incontinence and to look for alternative treatments: i) an α₁-adrenergic agonist that preferentially affects urethral over blood pressure was tested <i>in vivo</i>; ii) a modified cystometry model was developed for screening of muscarinic antagonists, by construction of a complete dose-response curve in each individual animal; iii) a new muscarinic antagonist, PNU-171990, was pharmacologically characterized <i>in vitro</i> and <i>in vivo</i>; iv) functional differences of the isomers of the muscarinic agonist BM-5 were characterized in the urinary bladder and ileum, <i>in vitro</i> and <i>in vivo</i>; v) the role of serotonin 5-HT_2A, 5-HT₃ and 5-HT₄ receptors were characterized on urinary bladder contractions <i>in vivo</i>.</p><p>In the search for urethra selective compounds, the α₁-adrenoceptors agonists phenylephrine and phenylpropanolamine selectively enhanced blood pressure as compared to the urethral pressure in rabbit. This is in contrast to the effect of oxymetazoline and NS-49. Muscarinic antagonists produced a dose-dependent inhibition of the volume-induced micturition pressure in the rat. PNU-171990, a non-selective muscarinic antagonist, revealed selectivity for urinary bladder pressure over salivation (P<0.05). (R)-BM-5 induced bladder contraction and saliva secretion in cats. The selective serotonin 5-HT_2A and 5-HT₃ receptor antagonists, ketanserin and tropisetron, both inhibited the effect of chemically induced bladder contraction in the anaesthetized cat.</p><p>In conclusion, an urethral-selective α_1A-adrenoceptor agonist may be a good treatment of stress incontinence. A bladder-selective competitive muscarinic antagonist is considered a good pharmacotherapy for overactive bladder. In addition, the 5-HT_2A and 5-HT₃receptor antagonist may improve lower urinary tract symptoms.</p>

Neurotrophic factors and their receptors are crucial for the formation of neuronal connections and for the neuronal survival during embryonic development of the nervous system. This has particularly been shown by studies of the PNS. The work of this thesis has aimed at clarifying where and when in the developing retina and its tectal target (as parts of the CNS), certain neurotrophic factors come into play. In a functional perspective, the focus has been on the possible involvement of these factors in the regulation of cell death / survival. Therefore, naturally occuring cell death in the developing avian retina was first studied. From the results, it is concluded that there is an early and a late phase of cell death in the developing retina. The cells dying during the early phase are proliferating retinal precursor cells, and the cells dying later are in the process of terminal differentiation. The timing and distribution of the dying cells suggest that the cell death is regulated. During retinal development two retinal cell types, amacrine cells and horizontal cells, express TrkA, a receptor for the neurotrophin nerve growth factor (NGF). These amacrine cells are shown to undergo cell death during the late cell death phase, but can be rescued by exogenous NGF. The horizontal cells in turn, are supported by NGF in an autocrine manner, and therefore survive. Two other neurotrophic factors brain-derived neurotrophic factor (BDNF) and glial cell-line derived neurotrophic factor (GDNF) are both expressed in the retina and in the target for retinal ganglion cells, the optic tectum. By the results, it is concluded that neuronal activity can regulate the expression of BDNF in the retina and optic tectum. Furthermore, GDNF can stimulate neurite outgrowth from retinal explants of a certain age. Taken together, the main result of this thesis is that neurotrophic factors indeed can work as autocrine survival factors in the developing CNS.

Members of the transforming growth factor-β (TGF-β) superfamily exhibit a range of effects on a host of different cell types. They signal through heteromeric complexes of serine/threonine kinase receptors of type I and type II. Gene targeted mutations of both factors and receptors have revealed that many of them are involved in early embryonic development. This thesis examines the receptors for this superfamily in the nervous system, especially bone morphogenetic protein receptor type II (BMPR-II). It was cloned from chicken nervous tissue, and its and other receptors’ expression in peripheral ganglia, spinal cord and brain of chicken, rat and mouse were examined. BMPR-II, ActR-II and ActR-IA were abundantly expressed throughout development in the nervous system, however with temporal regulation. One ligand of BMPR-II, BMP-7, was found to act synergistically with NT-3 and GDNF on subsets of peripheral neurons to promote survival and neurite outgrowth. A knock-in mouse was generated, encoding a truncated form of BMPR-II coupled to the endogenous tyrosine hydroxylase (TH) gene with an internal ribosome entry site (IRES). For ES-cell selection, a neomycin resistance gene was incorporated into the construct. Homozygous mice carrying the knock-in allele exhibited a small, hypokinetic phenotype. Levels of dopamine, noradrenaline and serotonin were measured, and the catecholamines were found to be lowered, dopamine as much as 97% in the caudate nucleus. The low catecholamine levels may not be an effect of the truncated BMPR-II, but rather a consequence of the knock-in construct reducing TH transcriptional rate. The TH hypomorphic mouse strain generated could find use as a model for catecholamine impaired systems, as seen in Parkinson’s disease.

Stress incontinence and overactive bladder are disorders with a common symptom, urinary incontinence, which is a serious medical and social handicap. Several neurotransmitters regulate the function of the lower urinary tract, including noradrenaline, acetylcholine, and serotonin. The present study is part of the search for pharmacological incontinence drugs. The aims of this thesis were to improve the existing pharmacological treatments of urinary incontinence and to look for alternative treatments: i) an α1-adrenergic agonist that preferentially affects urethral over blood pressure was tested in vivo; ii) a modified cystometry model was developed for screening of muscarinic antagonists, by construction of a complete dose-response curve in each individual animal; iii) a new muscarinic antagonist, PNU-171990, was pharmacologically characterized in vitro and in vivo; iv) functional differences of the isomers of the muscarinic agonist BM-5 were characterized in the urinary bladder and ileum, in vitro and in vivo; v) the role of serotonin 5-HT2A, 5-HT3 and 5-HT4 receptors were characterized on urinary bladder contractions in vivo. In the search for urethra selective compounds, the α1-adrenoceptors agonists phenylephrine and phenylpropanolamine selectively enhanced blood pressure as compared to the urethral pressure in rabbit. This is in contrast to the effect of oxymetazoline and NS-49. Muscarinic antagonists produced a dose-dependent inhibition of the volume-induced micturition pressure in the rat. PNU-171990, a non-selective muscarinic antagonist, revealed selectivity for urinary bladder pressure over salivation (P&lt;0.05). (R)-BM-5 induced bladder contraction and saliva secretion in cats. The selective serotonin 5-HT2A and 5-HT3 receptor antagonists, ketanserin and tropisetron, both inhibited the effect of chemically induced bladder contraction in the anaesthetized cat. In conclusion, an urethral-selective α1A-adrenoceptor agonist may be a good treatment of stress incontinence. A bladder-selective competitive muscarinic antagonist is considered a good pharmacotherapy for overactive bladder. In addition, the 5-HT2A and 5-HT3 receptor antagonist may improve lower urinary tract symptoms.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 7 uppsatser.