Association of Chronic Kidney Disease With Plasma NfL and Other Biomarkers of Neurodegeneration: The H70 Birth Cohort Study in Gothenburg

BACKGROUND AND OBJECTIVES: Studies associate chronic kidney disease (CKD) with neurodegeneration. This study investigated the relation between kidney function, blood, cerebrospinal fluid (CSF), and structural brain MRI markers of neurodegeneration, in a sample including individuals with and without CKD. METHODS: Participants from the Gothenburg H70 Birth Cohort Study, with data on plasma-neurofilament light (P-NfL), estimated glomerular filtration rate (eGFR) and structural brain MRI were included. Participants were invited to also have CSF collected. The primary endpoint of the present study was to determine any association between CKD and P-NfL. Secondary endpoints included cross-sectional associations between CKD, eGFR and cerebrospinal fluid (CSF)- and MRI-derived markers of neurodegeneration and Alzheimer's disease (AD) pathology (MRI: cortical thickness, hippocampal volume, lateral ventricle volume, white matter lesion volume; CSF: β-amyloid (Aβ) 42, Aβ42/40, Aβ42/p-tau, t-tau, p-tau, NfL). Participants with P-NfL and eGFR at baseline were re-examined on eGFR, 5.5 (5.3; 6.1) years (median; IQR) after the first visit, and the predictive value of P-NfL levels on incident CKD was estimated longitudinally, using a Cox proportional hazards model. RESULTS: We included 744 participants, 668 without CKD (Age 71 (70; 71) years, 50% males) and 76 with CKD (age 71 (70;71) years, 39% males). Biomarkers from cerebrospinal fluid (CSF) were analysed in 313 participants. 558 individuals returned for a re-examination of eGFR (75% response rate, age 76 (76; 77), 48% males, 76 new cases of CKD). Participants with CKD had higher P-NfL levels than those with normal kidney function (median; 18.8 versus 14.0 pg/mL, p<0.001), while MRI and CSF markers were similar between the groups. P-NfL was independently associated with CKD after adjustment for confounding variables, including hypertension and diabetes (OR; 3.231, p<0.001), in a logistic regression model. eGFR, and CSF Aβ 42/40: R=0.23, p=0.004 correlated in participants with Aβ42 pathology. P-NfL levels in the highest quartile were associated with incident CKD at follow-up (HR; 2.08 (1.14: 4.50)). DISCUSSION: In a community-based cohort of 70-year olds, P-NfL was associated with both prevalent and incident CKD, while CSF and/or imaging measures did not differ by CKD status. Participants with CKD and dementia presented similar levels of P-NfL

Subtypes of Alzheimer's Disease Display Distinct Network Abnormalities Extending Beyond Their Pattern of Brain Atrophy

Different subtypes of Alzheimer's disease (AD) with characteristic distributions of neurofibrillary tangles and corresponding brain atrophy patterns have been identified using structural magnetic resonance imaging (MRI). However, the underlying biological mechanisms that determine this differential expression of neurofibrillary tangles are still unknown. Here, we applied graph theoretical analysis to structural MRI data to test the hypothesis that differential network disruption is at the basis of the emergence of these AD subtypes. We studied a total of 175 AD patients and 81 controls. Subtyping was done using the Scheltens' scale for medial temporal lobe atrophy, the Koedam's scale for posterior atrophy, and the Pasquier's global cortical atrophy scale for frontal atrophy. A total of 89 AD patients showed a brain atrophy pattern consistent with typical AD; 30 patients showed a limbic-predominant pattern; 29 patients showed a hippocampal-sparing pattern; and 27 showed minimal atrophy. We built brain structural networks from 68 cortical regions and 14 subcortical gray matter structures for each AD subtype and for the controls, and we compared between-group measures of integration, segregation, and modular organization. At the global level, modularity was increased and differential modular reorganization was detected in the four subtypes. We also found a decrease of transitivity in the typical and hippocampal-sparing subtypes, as well as an increase of average local efficiency in the minimal atrophy and hippocampal-sparing subtypes. We conclude that the AD subtypes have a distinct signature of network disruption associated with their atrophy patterns and further extending to other brain regions, presumably reflecting the differential spread of neurofibrillary tangles. We discuss the hypothetical emergence of these subtypes and possible clinical implications

Protein and MRI profiling of genetic frontotemporal dementia

Frontotemporal dementia (FTD) is a group of neurodegenerative diseases with a wide range of symptoms such as loss of inhibition and social cognition, language impairment and motor dysfunction. Genetic FTD, characterized by mutations in one of several disease-causing genes, accounts for 10 - 30% of all cases of FTD. The most common causes for genetic FTD are repeat expansions in C9orf72 and mutations in GRN or MAPT, but there are also many other, rarer causes. Each mutation gives rise to a specific subtype of genetic FTD. These subtypes differ not only in clinical presentation, but also in the underlying pathophysiology. To be able to study, and eventually treat, genetic FTD a thorough understanding of the genetic subtypes is crucial. In this thesis we characterized the effects of a p.Ala417* mutation in TBK1, showing that it causes haploinsufficiency as well as demonstrating systemic effects on the K63 ubiquitination system. We also analyzed blood and cerebrospinal fluid samples from carriers of pathogenic mutations associated with genetic FTD to find biomarkers that can distinguish symptomatic mutation carriers from healthy controls or distinguish between the different genetic subtypes. We also studied how these biomarker candidates correlate with cortical and subcortical atrophy in genetic FTD. The results of these studies have provided a further understanding of genetic FTD as well as new biomarker candidates for several pathological processes

Genetic, magnetic resonance imaging and body fluid biomarker associations with severity of multiple sclerosis

Multiple sclerosis is a chronic and progressive neuroinflammatory disease that leads to demyelination and neurodegeneration in the central nervous system (CNS). Previous research has identified a wide range of environmental, lifestyle and genetic factors which increase MS susceptibility. However, the pathomechanisms that influence the severity of MS are largely unknown, and adequate biomarkers of disease severity are consequently lacking. Therefore, the aim of my thesis was to; 1) assess associations between the nerve injury biomarker neurofilament light (NfL) and brain atrophy and lesion volumes; 2) assess which brain/lesion volume measures show the strongest longitudinal association with clinical MS disability measures and to what degree these associations were affected by age; and to 3) identify genetic variants associated with brain atrophy, lesion volumes and plasma NfL (pNfL) levels in persons with MS. In Study I, we assessed how cerebrospinal fluid (CSF) and pNfL levels were associated with T1- and T2-lesion volumes as well as whole-brain, cortical and subcortical grey matter, white matter and thalamic volume fractions of total intracranial volume based on magnetic resonance imaging (MRI). High baseline CSF and pNfL levels were associated with lower whole-brain, subcortical grey matter, thalamic, white matter and corpus callosal volume fractions over time. A further analysis showed that there was an association between baseline pNfL and baseline cortical grey matter fractions also in absence of radiological signs of inflammatory disease activity. A topographic analysis of cortical thickness showed that loss of cortical volume preferentially involved frontotemporal cortical regions. These findings indicate that NfL levels contribute information about MS severity not provided by traditional MRI lesion metrics. In Study II, we showed that associations between baseline MRI variables, and baseline physical disability and self-reported impact of MS rapidly increased in strength in individuals beyond approximately 40-50 years of age. In separate longitudinal analyses using linear mixed-effects models, we showed that among the recorded brain volume measures, cortical and subcortical grey matter and thalamic volume fractions at baseline were the strongest predictors of future worsening in clinical disability over a median of approximately ten years’ follow-up time. They were also stronger predictors than T1- and T2-lesion volumes. In Study III, we assessed if a weighted risk score comprising 12 known MS risk human leukocyte antigen (HLA) alleles was associated with baseline and longitudinal MRI measures as described in Studies I and II. While this risk score was not significantly associated with baseline MRI measures, we found that a high score was associated with lower cortical grey matter fractions longitudinally. A further analysis showed that this effect was primarily driven by the HLA-DRB1*15:01 allele. These results suggest that MS HLA risk variants not only affect inflammatory, but also neurodegenerative aspects of the disease. In Studies IV and V, we performed genome-wide association studies of pNfL levels and whole-brain volume fractions, respectively, in persons with MS (and controls in Study IV). While no genome-wide significant associations were found in Study IV, gene set analyses highlighted a neural crest and odontogenesis development pathway in the regulation of pNfL levels, and a weighted MS susceptibility polygenic risk score was associated with higher pNfL levels in MS with statistical significance. These findings suggest that there is some degree of genetic regulation of pNfL levels, which partially overlap with MS risk. In Study V, we identified a genome-wide significant locus upstream of the glycerol kinase 2 (GK2) gene, previously implicated in the propensity for tobacco smoking, which is a known MS risk and severity factor. Gene set analyses in Study V also implicated Hypoxia Inducible Factor-1 (HIF1) in the regulation of whole-brain volume fractions, indicating that iron metabolism and response to hypoxia play a role in the neurodegenerative processes in MS

Alcohol consumption and cognition

There is evidence that alcohol consumption is increasing in recent decades, including both male and female older individuals. Excessive alcohol use can affect various functions, of which alcohol-related liver failure and cancer have mostly been the subject of research so far. However, it can also cause brain damage and cognitive impairment. At the same time, population aging also has an increased rate, which poses major challenges to the health care systems regarding age-related diseases such as cognitive impairment and dementia. In that work, we try to identify the role of alcohol in the clinical and demographic profile of individuals with mild cognitive impairment, investigate whether there are specific biomarkers for alcohol-related cognitive impairment in radiological imaging and performance on neuropsychological tests, and finally assess the diagnostic accuracy and clinical applicability of a specific screening instrument for delirium, which is a common condition among older individuals with cognitive impairment

Neural and behavioral plasticity in olfactory sensory deprivation

The human brain has a remarkable ability to reorganize as a consequence of altered demands. This ability is particularly noticeable when studying the neural effects of complete sensory deprivation. Both structural and functional cerebral reorganization have repeatedly been demonstrated in individuals with sensory deprivation, most evident in cortical regions associated with the processing of the absent sensory modality. Furthermore, sensory deprivation has been linked to altered abilities in remaining sensory modalities, often of a compensatory character. Although anosmia, complete olfactory sensory deprivation, is our most common sensory deprivation, estimated to affect around 5 % of the population, the effects of anosmia on brain and behavior are still poorly understood. The overall aim of this thesis was to investigate how the human brain and behavior are affected by anosmia, with a focus on individuals with congenital (lifelong) sensory deprivation. Specifically, Study I and Study IV assessed potential behavioral and neural multisensory compensatory abilities whereas Study II and Study III assessed potential reorganization beyond the processing of specific stimuli; the latter by determining morphological and resting-state functional connectivity alterations. Integration of information from different sensory modalities leads to a more accurate perception of the world around us, given that our senses provide complementary information. Although an improved ability to extract multisensory information would be of particular relevance to individuals deprived of one sensory modality, multisensory integration has been sparsely studied in relation to sensory deprivation. In Study I, multisensory integration of audio-visual stimuli was assessed in individuals with anosmia using two different experimental tasks. First, individuals with anosmia were better than matched controls in detecting multisensory temporal asynchronies in a simultaneity judgement task. Second, individuals with congenital, but not acquired, anosmia demonstrated indications of an enhanced ability to utilize multisensory information in an object identification task with degraded stimuli. Based on these results, the neural correlates of audio-visual processing and integration were assessed in individuals with congenital anosmia in Study IV. Relative to matched normosmic individuals, individuals with congenital anosmia demonstrated increased activity in established multisensory regions when integrating degraded audio-visual stimuli; however, no compensatory cross-modal processing in olfactory regions was demonstrated. Together, Study I and IV suggest that complete olfactory sensory deprivation is linked to enhanced audio-visual integration performance that might be facilitated by increased processing in multisensory regions. In Study II, whole-brain gray matter morphology was assessed in individuals with congenital anosmia. Both increases and decreases in the orbitofrontal cortex, a region associated with olfaction and sometimes referred to as secondary olfactory cortex, were observed in individuals with congenital anosmia in relation to matched controls. However, in contrast to our expectations, no sensory deprivation-dependent effects were demonstrated in piriform cortex, a region commonly referred to as primary olfactory cortex. Furthermore, Study III revealed an absence of differences in resting-state functional connectivity between individuals withcongenital anosmia and normosmic individuals within the primary olfactory cortex (including piriform cortex) as well as between core olfactory processing regions. In conclusion, the studies presented within this thesis suggest the existence of a potential multisensory compensatory mechanism in individuals with anosmia, but demonstrate a striking lack of morphological and functional alterations in piriform (primary olfactory) cortex. These results demonstrate that complete olfactory deprivation is associated with a distinct neural and behavioral reorganization in some regions but also a clear lack of effects in other regions; the latter underline the clear differences between our senses and suggest that extrapolating from individual senses should be done cautiously

Loneliness in adult people: its relationships with stress, health and hypothalamic-pituitary-adrenal axis functioning

Loneliness is one of the main issues in Western societies. Internet advances in recent years have made us a more connected society than ever, but despite this, loneliness is increasing. For survival and advancement, human beings need others to satisfy their needs for affection, belonging, and recognition. Thus, loneliness arises from the discrepancy between desired and actual social and intimate relationships. Research indicates that feelings of loneliness can be understood as a stressor, and it is related to several adverse consequences for physical and psychological health. This feeling can be experienced throughout life, although it is more frequent among the older population. All of this emphasizes the importance of studying loneliness and its influence on the well-being of our society. In this doctoral thesis, loneliness is addressed in relation to different stressors (Early Life Stress (ELS) and stress during adulthood) and different subjective (psychological, physical, and subjective cognitive decline (SCD)) and objective (basal Hypothalamic-Pituitary-Adrenal axis (HPA axis) functioning measures and biomarkers of Alzheimer’s Disease (AD) and Cerebrovascular Disease (CVD) pathology) health indicators in young, middle-aged, and older healthy people. The first chapter is a general introduction to the studies included in this thesis. Briefly, it describes the current literature on loneliness and its relationship with stress and health. In the first place, it presents the relationship between adverse experiences in the early stages of life and feelings of loneliness during adulthood. Likewise, it points out that loneliness can be understood as a stressor, and some studies that report its effects on physical and psychological health are presented. In addition, the literature on the relationship of both ELS and loneliness with the basal HPA axis functioning is reviewed because it is an important endocrine system involved in health and stress. Finally, the chapter describes the latest research on the possible role of loneliness in the context of SCD, suggested as the earliest preclinical stage of AD, and its relationship with early brain pathology of AD or CVD. The last part of the chapter includes the main aims and hypotheses of this doctoral thesis. The following three chapters describe the three studies in this doctoral thesis. Each of these chapters contains a brief introduction that describes the most important related literature, the specific methodology used and results found, and a discussion of the main findings. In the second chapter, the first study is explained. This study examines the role of loneliness as a mediator between early life stress and its relationship with the perception of stress and the basal HPA axis functioning during adulthood in healthy young and middle-aged people. In the third chapter, the second study is described, which analyzes loneliness and its association with subjective psychological and physical health and basal HPA axis functioning in healthy middle-aged and older people and whether these associations differ depending on sex. Finally, in this chapter, we explore the basal HPA axis functioning as an underlying mechanism in the relationship between loneliness and health. The fourth chapter includes the third study. This study investigates the role of loneliness in the context of SCD as a possible early indicator of AD and CVD in cognitively unimpaired older people. The fifth chapter discusses the main findings of the empirical studies mentioned above. The limitations and strengths of these studies are also discussed, as well as directions for future studies. The Sixth chapter includes the main conclusions. Finally, the seventh chapter consists of a summary of the present doctoral thesis in Valencian

Herramienta de gestión integral en innovación en imagen médica

La implementació de les Tecnologies de la informació i la Comunicació (TIC) i la digitalització de la imatge medica ha suposat un canvi en tot el progres clínic assistencial per part de radiòlegs i metges nuclears encarregats de realitzar l'informe diagnòstic i les intervencions radiològiques. Actualment, els sistemes d'informació coneguts com Picture Archiving and Communication System (PACS), Radiology Information System (RIS), i Hospital Information System (HIS) permeten el maneig dels estudis adquirits, el seu informat i el seguiment dels processos de gestió associats als fluxos de l'activitat assistencial. Propiciat per aquest profund canvi han nascut noves oportunitats i necessitats que, desafortunadament, no han sigut resoltes i integrades en la majoria dels entorns hospitalaris. Per exemple, gracies a la digitalització de la imatge i als avanços en investigació, és possible obtindré dades quantitatives de l'exploració adquirida que reflecteixen l'estat d'una malaltia o de l'efecte d'un fàrmac sobre aquesta. Aquestes mesures es coneixen com biomarcadors d'imatge. Per altra part, actualment els informes realitzats pels metges especialistes no tenen una estructura que impedisca una variabilitat en el contingut i en conseqüència l'absència potencial d'informació rellevant pel metge peticionari de l'exploració. El disseny i desenvolupament dels informes estructurats mitjançant l'ús de lèxics normalitzats i plantilles es factible amb les TIC. Aquests informes deuen establir-se per malalties i lesions concretes, i deuen estar consensuats entre els metges especialistes de la imatge i els metges peticionaris. Degut al volum de dades generades pels sistemes d'informació citats anteriorment, es crea contínuament una font de coneixement de dades que no son explotades. L'extracció d'aquest coneixement a través d'indicadors deu de permetre visualitzar l'estat actual dels serveis de radiologia i de medicina nuclear, de tal manera que es possibilite corregir els colls de botella i realitzar accions correctores oportunes front a una situació critica. El proposit final és promoure un funcionament òptim dels serveis i facilitar la presa de decisions fonamentades a les dades d'activitat que millor s'ajusten per a una millor atenció al pacient. Aquesta Tesi Doctoral té per objectiu l'integració eficient dels biomarcadors d'imatge, els informes estructurats, i els indicadors d'activitat en la pràctica assistencial dels serveis de radiologia i de medicina nuclear. Per aconseguir aquest objectiu s'utilitzaren estàndards d'imatge medica com el Digital Imaging and Communication in Medicine (DICOM) i altres com eXtensible Language Market (XML). Mitjançant la tecnologia JAVA es desenvolupà una plataforma per a la integració dels biomarcadors d'imatge. Mitjançant l'utilització de lèxics com el Systematized Nomenclature of Medicine - Clinical Terms (SNOMED-CT) i Radiology Lexicon (RADLEX), més l'estàndard DICOM i l'estàndard HML5, es va implantar una aplicació que permet l'integració de l'informe estructurat. D'aquesta manera es poden realitzar estudis poblacionals, així com analitzar la relació de determinats factors en una malaltia especifica. Per últim, de l'informació obtinguda del RIS i del PACS, es va construir una plataforma d'indicadors amb tecnologia JAVA per a permetre visualitzar l'estat dels serveis respecte a l'activitat assistencial; activitat d'innovació; i activitat d'investigació i docent. Per tant, la present Tesi Doctoral aporta als servicis de radiologia i de medicina nuclear una ferramenta d'innovació amb tres camps fonamentals per a oferir un millor diagnòstic, una millor cura i atenció al pacient. A través de la quantificació dels biomarcadors d'imatge i l'informe estructurat per a una medicina personalitzada, i amb els indicadors d'activitat per a una presa de decisions i d'accions basades en l'evidència.La implantación de las Tecnologías de la Información y la Comunicación (TIC) y la digitalización de la imagen médica supuso un cambio en todo el proceso clínico asistencial por parte de los radiólogos y médicos nucleares encargados de realizar el informe diagnóstico y las intervenciones radiológicas. Actualmente, los sistemas de información conocidos como Picture Archiving and Communication System (PACS), Radiology Information System (RIS), y Hospital Information System (HIS) permiten el manejo de los estudios adquiridos, su informado y el seguimiento de los procesos de gestión asociados a los flujos de la actividad asistencial. A raíz de este profundo cambio han nacido nuevas oportunidades y necesidades que, desafortunadamente, no han sido resueltas e integradas en la mayoría de los entornos hospitalarios. Por ejemplo, gracias a la digitalización de la imagen y a los avances en investigación, es posible obtener datos cuantitativos de la exploración adquirida que reflejen el estado de una enfermedad o el efecto de un fármaco sobre ella. Estas medidas se conocen como biomarcadores de imagen. Por otra parte, actualmente los informes realizados por los médicos especialistas carecen de un esqueleto que impida la variabilidad de contenido y en consecuencia la ausencia potencial de información relevante para el médico peticionario de la exploración. El diseño y desarrollo de los informes estructurados mediante el uso de léxicos normalizados y plantillas es factible con el uso de las TIC. Estos informes deben establecerse para enfermedades y lesiones concretas, y deben estar consensuados entre los médicos especialistas en la imagen y los médicos peticionarios. Debido a los volúmenes de datos generados por los sistemas de información citados anteriormente, se crea continuamente una fuente de conocimiento con datos no explotados. La extracción de este conocimiento a través de indicadores debe permitir visualizar el estado actual de los servicios de radiología y medicina nuclear, de tal forma que se posibilite corregir los cuellos de botella y realizar las acciones correctoras oportunas ante una situación crítica. El propósito final es promover un funcionamiento óptimo de los servicios y facilitar la toma de decisiones en base a los datos de actividad que mejor se ajusten para una mejor atención al paciente. Esta Tesis Doctoral tiene por justificación la integración eficiente de los biomarcadores de imagen, los informes estructurados, y los indicadores de actividad en la práctica asistencial de los servicios de radiología y medicina nuclear. Para lograr este objetivo se utilizaron estándares de imagen médica como el Digital Imaging and Communication in Medicine (DICOM) y otros como eXtensible Language Market (XML). A través de tecnología JAVA se desarrolló una plataforma para la integración de los biomarcadores de imagen. Mediante la utilización de léxicos como el Systematized Nomenclature of Medicine - Clinical Terms (SNOMED-CT) y Radiology Lexicon (RADLEX), más el estándar DICOM y el estándar HTML5, se implantó una aplicación que permite la integración del informe estructurado. De este modo se podrán realizar estudios poblacionales así como analizar la relación de determinados factores con una patología determinada. Por último, de la información obtenida del RIS y del PACS, se construyó una plataforma de indicadores con tecnología JAVA para permitir visualizar el estado de los servicios respecto a la actividad asistencial; actividad de innovación; y actividad científico-docente. Por tanto, la presente Tesis Doctoral aporta a los servicios de radiología y de medicina nuclear una herramienta de innovación en tres campos fundamentales para ofrecer un mejor diagnostico, cuidado y atención al paciente. A través de cuantificación de los biomarcadores de imagen y el informe estructurado para una medicina personalizada, y con los indicadores de actividad para una toma de deThe implementation of Information and Communication Technologies (ICT) and the digitization of medical images implies a change in the entire clinical care process for radiologists and nuclear physicians responsible for the diagnostic report and the radiological interventions. Nowadays, information systems such as Picture Archiving and Communication System (PACS), Radiology Information System (RIS) and Hospital Information System (HIS) enable the management of medical imaging studies, their reports and the follow-up of the management processes associated to the workflow of healthcare activities. These changes (use of ICT and digitization in hospitals) have created new opportunities and needs. Unfortunately, they have not been solved and integrated in most hospital settings. For example, thanks to the digitization of the image and research advances, it is possible to obtain quantitative data from the acquired exploration that reflect the state of a disease or the effect of a drug on it. These measures are known as image biomarkers. Reports made by specialist physicians currently lack of a skeleton that reduces the variability of content and consequently there are potential lack of relevant information for the applicant¿s physician. The design and development of structured reports using standard lexicon and templates is feasible with the use of ICT. These reports should be set up for diseases and specific injuries, and should be agreed upon between specialists and applicant¿s physicians. Due to the volume of data generated by the information systems mentioned above, a source of knowledge is continuously growing but data remains unexploited. The extraction of this knowledge through indicators could enable us to improve the processes in radiology and nuclear medicine departments which should help to correct bottlenecks and take corrective actions in critical situations. The final purpose is to promote the optimal functioning of the services departments and to facilitate the decision-making for a better attention to the patient care based on data activity. This Doctoral Thesis aims at integrating efficiently image biomarkers, structured reports and activity indicators into the clinical practice in the radiology and nuclear medicine departments. To achieve this goal, we have used medical imaging standards such as Digital Imaging and Communication in Medicine (DICOM) and eXtensible Language Market (XML). We used JAVA technology to develop a platform for the integration of image biomarkers. An application was implemented using lexicons such as the Systematized Nomenclature of Medicine - Clinical Terms (SNOMED-CT), Radiology Lexicon (RADLEX), the DICOM standard and the HTML5 standard. This application allows the integration of the structured report. In this way, it will be possible to make population studies, as well as to analyze the relation of certain factors with a certain disease. Finally, based on RIS and PACS data, a platform was developed using JAVA technology to provide the visualization of the status of key indicators of the performance of radiology departments; innovation activity; and research & teaching activities. This Doctoral Thesis provides the radiology and nuclear medicine departments with an innovative tool in three fundamental fields, offering a better diagnosis, health-care and attention to the patient. This has been done, using the quantification of image biomarkers and the structured report for a personalized medicine, and selecting those indicators of activity to make decisions based on data evidence.Ruiz Martínez, E. (2017). Herramienta de gestión integral en innovación en imagen médica [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/90429TESI

Importance of psychological factors in adrenocortical functioning and subjective memory complaints

El estrés ha sido considerado uno de los principales problemas de la sociedad actual, ya que se ha relacionado con diversas condiciones de salud mental y física, así como con enfermedades propias de la edad y problemas de memoria. Sin embargo, existen diferencias individuales en la forma en que las personas enfrentan situaciones estresantes. En este sentido, algunas personas, a pesar de estar expuestas a los mismos niveles de estrés, no desarrollan patologías, lo que sugiere que ciertos factores psicológicos podrían actuar como protectores de los efectos del estrés. La resiliencia, que engloba pensamientos positivos y optimistas, ha sido entendida como la capacidad de afrontar la adversidad y recuperarse de situaciones estresantes. Más importante aún, se ha propuesto como un factor importante asociado con una mejor salud y un envejecimiento exitoso. Entre los trastornos relacionados con la edad, se ha prestado mayor atención al deterioro cognitivo y la detección temprana de la demencia. La prioridad actual es estudiar qué factores podrían prevenir o retrasar el deterioro cognitivo. En este sentido, las Quejas Subjetivas de Memoria (QSM) a lo largo del tiempo, o el Deterioro Cognitivo Subjetivo (SCD), se han sugerido indistintamente como un proxy para la detección temprana de demencia en personas mayores. Sin embargo, estas QSM también aparecen en individuos jóvenes, lo que aumenta la necesidad de determinar qué factores podrían estar asociados con este fenómeno en las diferentes edades. Todo ello pone de relieve la importancia de estudiar cómo determinados factores psicológicos, especialmente los protectores, podrían estar relacionados con el estrés y las SMC a lo largo de la vida, pero especialmente en las personas mayores por ser una etapa de mayor vulnerabilidad tanto al estrés como a la pérdida de memoria. En esta tesis doctoral se abordan los dos principales temas de preocupación en las sociedades actuales, es decir, el estrés y la detección precoz de las demencias y cómo pueden afectarles diferentes factores psicológicos. Para ello, se han relacionado factores psicológicos de resiliencia (positividad, optimismo) y vulnerabilidad (pesimismo) con diferentes biomarcadores de estrés (saliva y cabello) y contextos (respuesta a un estresor y estrés crónico) en personas mayores sanas. En segundo lugar, la relación entre las QSM y diferentes factores de vulnerabilidad (ansiedad y depresión), factores protectores (resiliencia y positivismo), estrés (funcionamiento basal del eje hipotalámico pituitario suprarrenal [eje HPA]) y biomarcadores neurodegenerativos de la enfermedad de Alzheimer (EA) y Se han abordado las enfermedades cerebrovasculares (ECV). Este segundo objetivo general también se ha abordado en diferentes grupos de edad (es decir, jóvenes sanos, personas de mediana edad y mayores). En definitiva, esta tesis doctoral ayuda a clarificar el papel de algunos indicadores psicológicos y de estrés, con el fin de potenciar y fomentar futuras investigaciones e intervenciones enfocadas a la mejora de la salud y el envejecimiento saludable.Stress has been considered one of the main problems in today’s society, given that it has been related to several mental and physical health conditions, as well as age-related diseases and memory problems. However, there are individual differences in the way people face stressful situations. In this sense, some people, despite being exposed to the same levels of stress, do not develop pathologies, suggesting that certain psychological factors could act as protectors from the effects of stress. Resilience, which encompasses positive and optimistic thoughts, has been understood as the ability to face adversity and recover from stressful situations. More importantly, it has been proposed as an important factor associated with better health and successful aging. Among the age-related disorders, greater attention has been paid to cognitive decline and early dementia detection. The current priority is to study which factors could prevent or delay cognitive impairment. In this regard, Subjective Memory Complaints (SMCs) over time, or Subjective Cognitive Decline (SCD), have been indistinctly suggested as a proxy for early dementia detection in older people. However, these SMCs also appear in young individuals, increasing the need to determine which factors could be associated with this phenomenon at different ages. All of this highlights the importance of studying how certain psychological factors, especially protective factors, could be related to stress and SMCs across the lifespan, but especially in older people because it is a stage of greater vulnerability to both stress and memory decline. In this doctoral thesis, the two main issues of concern in today's societies are addressed, that is, stress and early detection of dementia and how different psychological factors can affect them. For this purpose, psychological factors of resilience (positivity, optimism) and vulnerability (pessimism) have been related to different stress biomarkers (saliva and hair) and contexts (response to a stressor and chronic stress) in healthy older people. Secondly, the relationship between SMCs and different vulnerability factors (anxiety and depression), protective factors (resilience and positivism), stress (basal functioning of the Hypothalamic Pituitary Adrenal axis [HPA axis]), and neurodegenerative biomarkers of Alzheimer’s disease (AD) and Cerebrovascular Disease (CVD) have been addressed. This second general objective has also been addressed in different age groups (i.e., healthy young, middle-aged, and older people). In sum, this doctoral thesis helps to clarify the role of some psychological and stress indicators, in order to enhance and encourage future research and interventions focused on improving health and healthy aging