Cortical microstructure in young onset Alzheimer's disease using neurite orientation dispersion and density imaging

Alzheimer's disease (AD) is associated with extensive alterations in grey matter microstructure, but our ability to quantify this in vivo is limited. Neurite orientation dispersion and density imaging (NODDI) is a multi-shell diffusion MRI technique that estimates neuritic microstructure in the form of orientation dispersion and neurite density indices (ODI/NDI). Mean values for cortical thickness, ODI, and NDI were extracted from predefined regions of interest in the cortical grey matter of 38 patients with young onset AD and 22 healthy controls. Five cortical regions associated with early atrophy in AD (entorhinal cortex, inferior temporal gyrus, middle temporal gyrus, fusiform gyrus, and precuneus) and one region relatively spared from atrophy in AD (precentral gyrus) were investigated. ODI, NDI, and cortical thickness values were compared between controls and patients for each region, and their associations with MMSE score were assessed. NDI values of all regions were significantly lower in patients. Cortical thickness measurements were significantly lower in patients in regions associated with early atrophy in AD, but not in the precentral gyrus. Decreased ODI was evident in patients in the inferior and middle temporal gyri, fusiform gyrus, and precuneus. The majority of AD-related decreases in cortical ODI and NDI persisted following adjustment for cortical thickness, as well as each other. There was evidence in the patient group that cortical NDI was associated with MMSE performance. These data suggest distinct differences in cortical NDI and ODI occur in AD and these metrics provide pathologically relevant information beyond that of cortical thinning

Relating diffusion tensor imaging measurements to microstructural quantities in the cerebral cortex in multiple sclerosis

To investigate whether the observed anisotropic diffusion in cerebral cortex may reflect its columnar cytoarchitecture and myeloarchitecture, as a potential biomarker for disease‐related changes, we compared postmortem diffusion magnetic resonance imaging scans of nine multiple sclerosis brains with histology measures from the same regions. Histology measurements assessed the cortical minicolumnar structure based on cell bodies and associated axon bundles in dorsolateral prefrontal cortex (Area 9), Heschl's gyrus (Area 41), and primary visual cortex (V1). Diffusivity measures included mean diffusivity, fractional anisotropy of the cortex, and three specific measures that may relate to the radial minicolumn structure: the angle of the principal diffusion direction in the cortex, the component that was perpendicular to the radial direction, and the component that was parallel to the radial direction. The cellular minicolumn microcircuit features were correlated with diffusion angle in Areas 9 and 41, and the axon bundle features were correlated with angle in Area 9 and to the parallel component in V1 cortex. This may reflect the effect of minicolumn microcircuit organisation on diffusion in the cortex, due to the number of coherently arranged membranes and myelinated structures. Several of the cortical diffusion measures showed group differences between MS brains and control brains. Differences between brain regions were also found in histology and diffusivity measurements consistent with established regional variation in cytoarchitecture and myeloarchitecture. Therefore, these novel measures may provide a surrogate of cortical organisation as a potential biomarker, which is particularly relevant for detecting regional changes in neurological disorders

Organización topológica de la corteza cerebral en el envejecimiento normal y en la enfermedad de Alzheimer

Programa de Doctorado en NeurocienciasLa corteza cerebral representa el más avanzado sistema de computación biológica que existe en la naturaleza. Su sofisticada organización anatómica y funcional facilita el procesamiento de la información en paralelo, de forma distribuida y jerarquizada; siendo precisamente su nivel de eficiencia uno de los aspectos que nos diferencia de otros mamíferos superiores. Estas propiedades emergentes pueden estudiarse in vivo mediante la aplicación de la Teoría de Grafos a los mapas cerebrales obtenidos con diferentes técnicas de neuroimagen. En este contexto, estudios previos han mostrado que las propiedades topológicas del cerebro humano varían en función del número de regiones incluidas en el grafo, añadiendo un grado de incertidumbre a los resultados obtenidos con esta aproximación analítica. Además, el envejecimiento se caracteriza por una serie de cambios anátomo-funcionales en la corteza cerebral que alteran su organización topológica, lo cual podría afectar a la relación entre los patrones de conectividad estructural y funcional, aspectos que podrían sufrir un deterioro adicional durante el proceso de neurodegeneración que acompaña a la enfermedad de Alzheimer (EA). El presente trabajo de Tesis trata de arrojar luz sobre estas cuestiones. Para ello, se han adquirido imágenes cerebrales de resonancia magnética estructural (RM) y de tomografía por emisión de positrones (PET) con el radiotrazador 18F-fluorodeoxiglucosa (FDG) en 29 personas mayores cognitivamente sanas, 29 personas mayores con deterioro cognitivo leve tipo amnésico (DCLa) y 29 pacientes con EA leve. A partir de estas imágenes, se han construido redes estructurales y funcionales de la corteza cerebral para posteriormente determinar si los cambios observados en su organización topológica y en las propiedades de sus nodos permiten caracterizar la transición entre el envejecimiento normal y el patológico. Nuestros resultados confirman, en primer lugar, que la organización topológica de la red cortical estructural cambia significativamente con la escala de parcelación, demostrándose que las parcelaciones óptimas son aquellas compuestas por regiones corticales de aproximadamente 250 mm2 de superficie. En segundo lugar, los resultados indican que la conectividad local es un rasgo predominante en el envejecimiento normal, siendo las áreas sensoriomotoras y visuales las que presentan un mayor nivel de segregación. Por otra parte, las conexiones de larga distancia y la capacidad de integración cortical se restringen a regiones de asociación heteromodales, que mostraron una mayor vulnerabilidad ante ataques simulados de la red. Tal como cabría esperar, este patrón de conectividad estructural guarda una estrecha relación con el patrón de conectividad funcional de personas mayores sanas. Por el contrario, los individuos con DCLa y los pacientes con EA mostraron una organización topológica de la corteza cerebral menos eficiente, caracterizada por la presencia de elementos más aislados a nivel global, hemisférico y lobular, lo cual además de favorecer la segregación reduce la capacidad de integración del sistema cortical. Este deterioro de la conectividad estructural y funcional produce además una disminución del acoplamiento local y un aumento del acoplamiento global entre ambas redes. En conjunto, nuestros resultados muestran cómo la topología de la red cortical y los atributos de sus nodos se alteran progresivamente desde el envejecimiento normal hasta llegar a la EA. En la era de la medicina personalizada y en una sociedad marcadamente envejecida, se espera que en un futuro no tan lejano estas aproximaciones contribuyan a mejorar el diagnóstico temprano de la EA así como de otras patologías neurodegenerativas asociadas al envejecimiento.Universidad Pablo de Olavide. Departamento de Fisiología, Anatomía y Biología Celula

MRI-based brain morphometry correlates of chronic pain in knee osteoarthritis

Chronic pain is a complex experience that involves sensory, emotional, and cognitive aspects. The neurobiological mechanisms are therefore expected to be complex, widespread and largely maladaptive. Recent research of neuroimaging in chronic pain suggests cerebral re-organization on a structural level as a consequence of chronic pain. However, a combined and large-scale brain morphological profile in chronic pain to investigate its neural substrates has not been elucidated. The research presented aims to investigate morphological brain correlates and putatively related behavioural and cognitive aspects of chronic pain due to primary nociceptive knee osteoarthritic disorder using advanced imaging techniques for manual, voxel-based, and surface-based analysis, and questionnaire-based participants’ characterization. 31 participants with chronic painful knee osteoarthritis (age= 64.6± 8.4 years, 15 females, mean duration of pain=9.6 years) and 22 healthy controls (age= 61.3± 7.5, 13 females) underwent high-resolution anatomical MRI at 3 Tesla, and detailed pain characterization and psychometric assessment. Findings from this thesis challenge the common belief that chronic pain leads to hippocampal volume reduction and allegedly cognitive dysfunction. Indeed, general cognitive function and delayed recall memory were normally preserved in the studied cohort, and moreover the hippocampal volume was significantly enlarged. The volume of the rostral part (emotional) of anterior cingulate showed significant positive correlation with pain catastrophizing behaviour suggesting that it may underlie the pain catastrophizing tendency in patients with chronic knee pain. Higher scores of mechanical pain sensitivity correlated with reduced cortical thickness in the anterior cingulate indicating its potential key role in the process of central pain sensitization. Sufferers of chronic knee OA pain exhibited less grey matter volume in the left dorsolateral prefrontal cortex, which has a modulatory role in nociceptive transmission namely, pain perception inhibitory effect. Although the mechanism of this reduction is unknown, such a change may suggest functional disturbance with subsequent aberrant contribution to pain sustainability and chronification. Whole brain cortical thickness was investigated in patients and results revealed wide spread cortical thinning progresses with pain duration, preferentially in females, and in areas largely outside the known pain matrix, but including the posterior default mode network. Finally, preliminary results from investigating the potential mechanism of chronic pain related neocortical plasticity will be presented that may provide framework for future studies

MRI-based brain morphometry correlates of chronic pain in knee osteoarthritis

Chronic pain is a complex experience that involves sensory, emotional, and cognitive aspects. The neurobiological mechanisms are therefore expected to be complex, widespread and largely maladaptive. Recent research of neuroimaging in chronic pain suggests cerebral re-organization on a structural level as a consequence of chronic pain. However, a combined and large-scale brain morphological profile in chronic pain to investigate its neural substrates has not been elucidated. The research presented aims to investigate morphological brain correlates and putatively related behavioural and cognitive aspects of chronic pain due to primary nociceptive knee osteoarthritic disorder using advanced imaging techniques for manual, voxel-based, and surface-based analysis, and questionnaire-based participants’ characterization. 31 participants with chronic painful knee osteoarthritis (age= 64.6± 8.4 years, 15 females, mean duration of pain=9.6 years) and 22 healthy controls (age= 61.3± 7.5, 13 females) underwent high-resolution anatomical MRI at 3 Tesla, and detailed pain characterization and psychometric assessment. Findings from this thesis challenge the common belief that chronic pain leads to hippocampal volume reduction and allegedly cognitive dysfunction. Indeed, general cognitive function and delayed recall memory were normally preserved in the studied cohort, and moreover the hippocampal volume was significantly enlarged. The volume of the rostral part (emotional) of anterior cingulate showed significant positive correlation with pain catastrophizing behaviour suggesting that it may underlie the pain catastrophizing tendency in patients with chronic knee pain. Higher scores of mechanical pain sensitivity correlated with reduced cortical thickness in the anterior cingulate indicating its potential key role in the process of central pain sensitization. Sufferers of chronic knee OA pain exhibited less grey matter volume in the left dorsolateral prefrontal cortex, which has a modulatory role in nociceptive transmission namely, pain perception inhibitory effect. Although the mechanism of this reduction is unknown, such a change may suggest functional disturbance with subsequent aberrant contribution to pain sustainability and chronification. Whole brain cortical thickness was investigated in patients and results revealed wide spread cortical thinning progresses with pain duration, preferentially in females, and in areas largely outside the known pain matrix, but including the posterior default mode network. Finally, preliminary results from investigating the potential mechanism of chronic pain related neocortical plasticity will be presented that may provide framework for future studies