Characterizing cognitive aging through multimodal MRI and NIBS: influence of education and gene expression

Abstract

The thesis entitled "Characterizing cognitive aging through multimodal MRI and NIBS: influence of education and gene expression" is based on the knowledge that the aging population is increasing throughout the world. This leads to an increase in cases of dementia, such as Alzheimer's disease and other pathologies that generate disability. However, there is strong evidence that healthy aging is also possible from a cognitive point of view. For this reason, the research challenge for the coming decades focuses on the development of new prevention strategies and, as this work has done, on the characterization of this cognitively preserved elderly population.

Neuroimaging studies based on magnetic resonance imaging (MRI) show that physiological aging is characterized by generalized brain atrophy, but that it occurs unequally between regions and between subjects. Functional MRI (fMRI) findings also are in line with this heterogeneity, showing both reductions and increases in brain activity. In addition, there is high variability in the cognitive profile of older people and two non-mutually exclusive pathways have been proposed to explain why some aged people are able to achieve high cognitive performance: cognitive reserve (CR) and brain maintenance (BM). Currently, these two theoretical concepts are described as macroscopic constructs and are not linked to identifiable biological mechanisms through which their beneficial effect would be explained in terms of adaptability to cope with (i.e., CR) or the ability to not experience age-related brain changes (i.e., BM). In light of all this, the use of new technologies that allow us to understand the mechanisms related to optimal brain function in advanced ages becomes vital. Thus, the objective of this Doctoral Thesis was to characterize the brain substrates underlying healthy cognitive aging and reveal how CR estimates can modulate the relationship between the measures studied.

The present work consists of four studies that were carried out in order to answer the above-mentioned objective. The Doctoral Thesis included data from more than 100 healthy elderly, using cross-sectional and longitudinal measures of cognition and variables derived from multimodal MRI analysis. Furthermore, we incorporate a novel methodology based on transcriptional architecture analysis using regional whole-brain gene expression data from the Allen Brain Human Atlas. Finally, an intervention was performed that combined transcranial direct current stimulation (tDCS) with fMRI.

From different MRI modalities, our results revealed neuroprotective and compensatory effects of CR that support preserved cognition, and that appears to be related to differential associations between age and measures of gray and white matter integrity. Specifically, CR was associated with increased thickness of the prefrontal cortex, and this structural benefit was linked to a gene expression profile characterized by a relative up-regulation of a set of genes involved in cell communication, neurotransmission, and immune response, thus proposing some biological mechanisms related to plastic phenomena through which CR could act. From fMRI analyses, we identified that cognitive decline was associated with increases in brain activity in areas unrelated to assessed function in the presence of higher structural atrophy. Finally, combining fMRI and tDCS, we show how non-invasive brain stimulation was able to reverse this over-activation detected longitudinally in those subjects with cognitive decline.

Thus, from a multimodal approach in elderly subjects, we were able to describe those anatomical-functional and molecular characteristics that underlay a successful cognitive performance. In addition, this work has helped to clarify part of the mechanisms of neuroprotection, compensation, and stability in aging.

Envellir de manera saludable és possible, també des del punt de vista cognitiu. Estudis previs basats en dades de Ressonància Magnètica (RM) han evidenciat que algunes persones grans poden mantenir preservada la seva funció cognitiva perquè no experimenten canvis cerebrals. Tot i això, tenir un alt rendiment cognitiu durant la vellesa és possible mitjançant mecanismes compensatoris que permeten contrarestar el dany cerebral sofert per l'edat (teoria de la Reserva Cognitiva; RC). En aquest context, el principal objectiu de la present Tesi Doctoral va ser caracteritzar els substrats cerebrals estructurals i funcionals subjacents a un envelliment cognitiu saludable, així com revelar com la RC pot modular la relació entre les mesures estudiades. Per això, es van realitzar un total de 4 estudis en una població d'edat avançada cognitivament sana, usant enfocaments transversals i longitudinals de RM, i altres eines innovadores com la caracterització de l'expressió gènica de regions corticals utilitzant o l'estimulació cerebral no invasiva combinada amb RM. Els nostres resultats van demostrar que nivells més elevats de RC (mesurats com anys d'educació) s'associen amb un rendiment cognitiu alt, però no amb un manteniment d'aquest. Vam poder detectar que els efectes compensatoris i neuroprotectors de la RC coexisteixen a l'envelliment. Altes estimacions de RC es van relacionar amb un gruix cortical més gran (neuroprotecció) en àrees prefrontals que, al seu torn, es van associar amb una expressió a l'alça de gens involucrats en mecanismes biològics que podrien explicar l'efecte protector de la RC. A més, l'ús de RM funcional ens va permetre establir que els subjectes que mantenen un alt rendiment mostren patrons estables d'activació, mentre que els que declinen mostren major atròfia estructural i intents fracassats de compensació funcional. No obstant això, aquests subjectes declinadors són els que van mostrar un efecte més gran de l'estimulació cerebral no invasiva, evidenciant una normalització del patró funcional. Així, a partir de l'estudi multimodal de l'envelliment, hem descrit aquelles característiques anatomofuncionals i moleculars subjacents al rendiment cognitiu exitós, un coneixement útil per a la prevenció i el disseny de futures intervencions per promoure la salut cerebral en edats avançades.