Estudio clínico y de neuroimagen de la función noradrenérgica como indicador precoz de deterioro cognitivo

[spa] Los trastornos neurocognitivos (TNC) son un grupo heterogéneo de entidades clínicas cuya característica principal es el deterioro de todas o algunas de las capacidades funcionales y cognitivas previamente adquiridas por el individuo. Entre ellos encontramos el TNC mayor, tener múltiples etiologías, su causa más común es la enfermedad de Alzheimer (EA). Las marcas neuropatológicas distintivas de esta patología son la acumulación de placas de proteína β-amiloide y la de proteína tau hiperfosforilada que forma, entre otros, ovillos neurofibrilares. El primer lugar en el que se han detectado cambios en el proceso de formación de estas acumulaciones es el locus coeruleus (LC). Este es un núcleo situado en el tegmento pontino y es la mayor fuente de noradrenalina del sistema nervioso central. La integridad estructural del LC se ha investigado tanto en EA como en población en riesgo de desarrollar EA, sin embargo la preservación funcional de este núcleo a lo largo del continuum del TNC restaba sin estudiar. En esta tesis se presentan dos estudios centrados en la evaluación de la conectividad funcional entre el LC y diferentes regiones corticales y subcorticales, en grupos en riesgo de EA: hijos de pacientes con EA de inicio tardío (H-EAIT), individuos con deterioro cognitivo leve (DCL) y pacientes con trastorno depresivo mayor en edad avanzada (TDM); con el fin de comprobar si la medición de la funcionalidad del LC puede constituir un marcador precoz del comienzo del proceso neurodegenerativo en estas etapas tempranas del TNC. El primer estudio se centra en analizar la conectividad del LC en un grupo de H- EAIT, en comparación con sujetos sanos, durante una secuencia de resonancia magnética funcional en estado de reposo. En el segundo estudio se incluyó un grupo de DCL, de TDM y un grupo control; y se estudió la conectividad del LC durante la realización de una tarea oddball o de detección de estímulos, que permite estudiar la actividad neuronal del LC. En ambos casos correlacionamos los resultados de los análisis de neuroimagen con medidas clínicas, neuropsicológicas y conductuales, con el fin de caracterizar los patrones de alteración funcional y su asociación con posibles variables clínicas o cognitivas. Nuestros resultados apuntan a la disminución de la conectividad global del LC en el grupo de H-EAIT durante el estado de reposo y en TDM ante la detección de estímulos salientes (oddball). En ambos grupos observamos una disminución de la conectividad entre el LC y regiones del cerebelo posterior, implicadas en la modulación de la actividad de la red por defecto, de control ejecutivo y de saliencia. Igualmente, el grupo de TDM se caracteriza por presentar una disminución de la conectividad entre el LC y el giro fusiforme y la corteza cingulada anterior (CCA) ante los estímulos oddball. En los H-EAIT encontramos una correlación positiva entre la conectividad del LC-cerebelo posterior y medidas de recuerdo diferido que señala la implicación de este patrón en la función mnésica. Además, encontramos una asociación negativa entre la severidad de síntomas depresivos y la conectividad LC-cerebelo posterior. En los TDM, la conectividad LC-CCA se asocia negativamente con medidas de severidad y carga del trastorno depresivo, reflejo de la diferenciación entre dos subgrupos de pacientes depresivos: en episodio activo de depresión y en remisión. Los resultados de este estudio confirman que existen alteraciones en la conectividad del LC en estadios iniciales del TNC y en población con un riesgo incrementado de desarrollo de EA. Además, apoyan la modulación del LC de regiones corticales y subcorticales implicadas en función mnésica, atencional y regulación del arousal. Esta tesis supone un punto de base para la investigación más profunda del LC a lo largo del continuo del TNC, con el fin de poder desarrollar herramientas diagnósticas no invasivas que permitan detectar precozmente procesos neurodegenerativos y el desarrollo de tratamientos más personalizados.[eng] Neurocognitive disorders (NCD) are a heterogeneous group of clinical entities that share as a principal hallmark the impairment in all or some of the previously acquired cognitive and functional capacities. Among this group, Alzheimer’s disease (AD) is the most prevalent cause of NCD. The two biological hallmarks of AD are the β-amyloid plaques and hyperphosphorylated tau neurofibrillary tangles. The locus coeruleus (LC) nucleus, the major source of noradrenaline to the central nervous system, is the region where pathological changes start in the continuum of AD. Structural integrity of this nucleus has been investigated in AD and AD at-risk population, but its functional preservation remained unstudied. In this thesis, we present two studies focused in the LC functional connectivity. The first study included a group of offspring of late onset AD (O-LOAD) and we used a resting-state functional magnetic resonance (rs-fMRI). For the second study a group of mild cognitive impairment (MCI) and late-life major depressive disorder (MDD) were recruited and they performed an oddball task during the acquisition of functional magnetic resonance imaging (fMRI). In both works, neuroimaging results were correlated with clinical, neuropsychological and behavioral data. Firstly, we found that both O-LOAD and MDD groups showed a diminished LC global connectivity, and these groups also presented a lower connectivity between LC and posterior cerebellum regions, during rs-fMRI and the oddball task, respectively. Moreover, MDD showed a lower connectivity between LC and fusiform gyrus and anterior cingulate cortex (ACC) in front of oddball stimuli. In O-LOAD we observed a negative association between LC-posterior cerebellum and depression symptoms and memory measures; and MDD showed an inverse correlation between LC-CCA connectivity and depression severity and the number of episodes measures. Our results point to the presence of connectivity alterations of LC in early stages of NCD and in AD at- risk population. A deeper investigation of functional activity and connectivity of the LC through the NCD continuum would be useful for the development of non-invasive diagnostic tools and the development of personalized treatments

Diagnosis of late-life depression using estructural equation modeling and dynamic effective connectivity during resting fMRI

Background: Late-life depression (LLD) is characterized by cognitive and social impairments. Determining neurobiological alterations in connectivity in LLD by means of fMRI may lead to a better understanding of the neural basis underlying this disorder and more precise diagnostic markers. The primary objective of this paper is to identify a structural model that best explains the dynamic effective connectivity (EC) of the default mode network (DMN) in LLD patients compared to controls. Methods: Twenty-seven patients and 29 healthy controls underwent resting-state fMRI during a period of eight minutes. In both groups, jackknife correlation matrices were generated with six ROIs of the DMN that constitute the posterior DMN (pDMN). The different correlation matrices were used as input to estimate each structural equation model (SEM) for each subject in both groups incorporating dynamic effects. Results: The results show that the proposed LLD diagnosis algorithm achieves perfect accuracy in classifying LLD patients and controls. This differentiation is based on three aspects: the importance of ROIs 4 and 6, which seem to be the most distinctive among the subnetworks; the shape that the specific connections adopt in their networks, or in other words, the directed connections that are established among the ROIs in the pDMN for each group; and the number of dynamic effects that seem to be greater throughout the six ROIs studied [t = 54.346; df = 54; p < .001; 95 % CI difference = 5.486-5.906]. Limitations: The sample size was moderate, and the participants continued their current medications. Conclusions: The network models that we developed describe a pattern of dynamic activation in the pDMN that may be considered a possible biomarker for LLD, which may allow early diagnosis of this disorder

Locus coeruleus connectivity alterations in late-life major depressive disorder during a visual oddball task

The Locus Coeruleus (LC) is the major source of noradrenergic neurotransmission. Structural alterations in the LC have been observed in neurodegenerative disorders and at-risk individuals, although functional connectivity studies between the LC and other brain areas have not been yet performed in these populations. Patients with late-life major depressive disorder (MDD) are indeed at increased risk for neurodegenerative disorders, and here we investigated LC connectivity in late-life MDD in comparison to individuals with amnestic type mild cognitive impairment (aMCI) and healthy controls (HCs). We assessed 20 patients with late-life MDD, 16 patients with aMCI, and 26 HCs, who underwent a functional magnetic resonance scan while performing a visual oddball task. We assessed task-related modulations of LC connectivity (i.e., Psychophysiological Interactions, PPI) with other brain areas. A T1-weighted fast spin-echo sequence for LC localization was also obtained. Patients with late-life MDD showed lower global connectivity during target detection in a cluster encompassing the right caudal LC. Specifically, we observed lower LC connectivity with the left anterior cingulate cortex (ACC), the right fusiform gyrus, and different cerebellar clusters. Moreover, alterations in LC-ACC connectivity correlated negatively with depression severity (i.e., Geriatric Depression Scale and number of recurrences). Reduced connectivity of the LC during oddball performance seems to specifically characterize patients with late-life MDD, but not other populations of aged individuals with cognitive alterations. Such alteration is associated with different measures of disease severity, such as the current presence of symptoms and the burden of disease (number of recurrences)

Locus coeruleus connectivity alterations in late-life major depressive disorder during a visual oddball task

The Locus Coeruleus (LC) is the major source of noradrenergic neurotransmission. Structural alterations in the LC have been observed in neurodegenerative disorders and at-risk individuals, although functional connectivity studies between the LC and other brain areas have not been yet performed in these populations. Patients with late-life major depressive disorder (MDD) are indeed at increased risk for neurodegenerative disorders, and here we investigated LC connectivity in late-life MDD in comparison to individuals with amnestic type mild cognitive impairment (aMCI) and healthy controls (HCs). We assessed 20 patients with late-life MDD, 16 patients with aMCI, and 26 HCs, who underwent a functional magnetic resonance scan while performing a visual oddball task. We assessed task-related modulations of LC connectivity (i.e., Psychophysiological Interactions, PPI) with other brain areas. A T1-weighted fast spin-echo sequence for LC localization was also obtained. Patients with late-life MDD showed lower global connectivity during target detection in a cluster encompassing the right caudal LC. Specifically, we observed lower LC connectivity with the left anterior cingulate cortex (ACC), the right fusiform gyrus, and different cerebellar clusters. Moreover, alterations in LC-ACC connectivity correlated negatively with depression severity (i.e., Geriatric Depression Scale and number of recurrences). Reduced connectivity of the LC during oddball performance seems to specifically characterize patients with late-life MDD, but not other populations of aged individuals with cognitive alterations. Such alteration is associated with different measures of disease severity, such as the current presence of symptoms and the burden of disease (number of recurrences)

Lower Locus Coeruleus MRI intensity in patients with late-life major depression

Background: The locus coeruleus (LC) is the major noradrenergic source in the central nervous system. Structural alterations in the LC contribute to the pathophysiology of different neuropsychiatric disorders, which may increase to a variable extent the likelihood of developing neurodegenerative conditions. The characterization of such alterations may therefore help to predict progression to neurodegenerative disorders. Despite the LC cannot be visualized with conventional magnetic resonance imaging (MRI), specific MRI sequences have been developed to infer its structural integrity. Methods: We quantified LC signal Contrast Ratios (LCCRs) in late-life major depressive disorder (MDD) (n = 37, 9 with comorbid aMCI), amnestic Mild Cognitive Impairment (aMCI) (n = 21, without comorbid MDD), and healthy controls (HCs) (n = 31), and also assessed the putative modulatory effects of comorbidities and other clinical variables. Results: LCCRs were lower in MDD compared to aMCI and HCs. While no effects of aMCI comorbidity were observed, lower LCCRs were specifically observed in patients taking serotonin/norepinephrine reuptake inhibitors (SNRIs). Conclusion: Our results do not support the hypothesis that lower LCCRs characterize the different clinical groups that may eventually develop a neurodegenerative disorder. Conversely, our results were specifically observed in patients with late-life MDD taking SNRIs. Further research with larger samples is warranted to ascertain whether medication or particular clinical features of patients taking SNRIs are associated with changes in LC neurons

Medidas contra la planificación fiscal agresiva: Las normas generales antiabuso

Tal y como indica el título, el objetivo de este trabajo será mostrar cómo se ha logrado avanzar en la lucha contra la planificación fiscal agresiva, sobre todo a nivel supranacional. Para ello, inicialmente se hará referencia al concepto en sí de la planificación fiscal, mostrando la delgada línea que la separa de la agresiva, cómo las empresas consiguen aprovecharse de ello y realizan prácticas abusivas e ilícitas. Pero eso será solamente una contextualización de la situación, ya que el grueso de este trabajo consistirá en la explicación de las medidas que se han llevado a cabo para luchar contra este fenómeno, es decir, la reacción de las organizaciones supranacionales para poder combatir contra ello. Entre dichas medidas nos centraremos en las tomadas por la UE (Directiva anti-elusión) y la OCDE (Plan de Acción BEPS), especialmente en la norma general antiabuso de la Directiva y el PPT incluido en la acción 6 del Plan, intentado analizarlas y ver el impacto que han tenido en el ámbito tributario

Abnormalities in the default mode network in late-life depression: A study of resting-state fMRI

Background/Objective: Neuroimaging studies have reported abnormalities in the examination of functional connectivity in late-life depression (LLD) in the default mode network (DMN). The present study aims to study resting-state functional connectivity within the DMN in people diagnosed with late-life major depressive disorder (MDD) compared to healthy controls (HCs). Moreover, we would like to differentiate these same connectivity patterns between participants with high vs. low anxiety levels. Method: The sample comprised 56 participants between the ages of 60 and 75; 27 of them were patients with a diagnosis of MDD. Patients were further divided into two samples according to anxiety level: the four people with the highest anxiety level and the five with the lowest anxiety level. Clinical aspects were measured using psychological questionnaires. Each participant underwent functional magnetic resonance imaging (fMRI) acquisition in different regions of interest (ROIs) of the DMN. Results: There was a greater correlation between pairs of ROIs in the control group than in patients with LLD, being this effect preferentially observed in patients with higher anxiety levels. Conclusions: There are differences in functional connectivity within the DMN depending on the level of psychopathology. This can be reflected in these correlations and in the number of clusters and how the brain lateralizes (clustering)

Functional Connectivity of the Locus Coeruleus Identifies Individuals at Familial Risk for Alzheimer's Disease

Background: Prevention and early treatment strategies for Alzheimer´s Disease (AD) are hampered by the lack of risk biomarkers. Neuropsathological changes in de Locus Coeruleus (LC) are detected early in AD, and noradrenaline plays a neuroprotective role in LC projecting areas. We assessed functional connectivity (FC) of the brainstem in asymptomatic individuals at familial risk for AD hypothesizing that FC of the LC will be decreased in relation to non-at-risk individuals. Methods: 31 offspring of patients with late-onset AD (O-LOAD) and 28 controls underwent a neuropsychological evaluation and a resting state functional MRI acquisition. In FC analysses we evaluated whole-brain global connectivity of the brainstem area, and subsequently assessed seed-to-voxel FC patterns from regions showing between-group differences.Results: O-LOAD scored worse in the MMSE and the RAVLT verbal recognition and delayed recall (pFDR<0.05). In imaging analyses, we identified a cluster encompassing the left LC (peak=-4, -34, -32, PTFCE<0.05) showing a decreased global connectivity and a positive correlation with verbal delayed recall scores in O-LOAD subjects (r=0.441, p=0.035). Seed-to-voxel analyses revealed that above findings were largely explained by decreased LC-cerebellar connectivity. Specifically, FC between the LC and the left Crus 1 correlated positively with verbal delayed recall in the O-LOAD group (r=0.464, p=0.022).Conclusions: FC between the LC and the cerebellar cortex is decreased in the healthy offspring of patients with LOAD, such connectivity measurements being associated with verbal memory scores. FC between the LC and the cerebellum may eventually enable the development of prevention and early treatment strategies in AD.Fil: del Cerro, Inés. Universidad de Barcelona. Hospital Duran I Reynals. Instituto de Investigación Biomédica de Bellvitge; EspañaFil: Villarreal, Mirta Fabiana. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Abulafia, Carolina Andrea. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Duarte Abritta, Barbara Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Sanchez, Stella Maris. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Castro, Mariana Nair. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bocaccio, Hernan. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ferrer, Isidro. Universidad de Barcelona. Hospital Duran I Reynals. Instituto de Investigación Biomédica de Bellvitge; EspañaFil: Menchón, José M.. Universidad de Barcelona. Hospital Duran I Reynals. Instituto de Investigación Biomédica de Bellvitge; EspañaFil: Sevlever, Gustavo. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Soriano Mas, Carles. Universidad de Barcelona. Hospital Duran I Reynals. Instituto de Investigación Biomédica de Bellvitge; EspañaFil: Guinjoan, Salvador Martín. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina74th Annual Scientific Convention and MeetingChicagoEstados UnidosSociety of Biological Psychiatr