Quantification of white matter cellularity and damage in preclinical and early symptomatic Alzheimer\u27s disease

Interest in understanding the roles of white matter (WM) inflammation and damage in the pathophysiology of Alzheimer disease (AD) has been growing significantly in recent years. However, in vivo magnetic resonance imaging (MRI) techniques for imaging inflammation are still lacking. An advanced diffusion-based MRI method, neuro-inflammation imaging (NII), has been developed to clinically image and quantify WM inflammation and damage in AD. Here, we employed NII measures in conjunction with cerebrospinal fluid (CSF) biomarker classification (for β-amyloid (Aβ) and neurodegeneration) to evaluate 200 participants in an ongoing study of memory and aging. Elevated NII-derived cellular diffusivity was observed in both preclinical and early symptomatic phases of AD, while disruption of WM integrity, as detected by decreased fractional anisotropy (FA) and increased radial diffusivity (RD), was only observed in the symptomatic phase of AD. This may suggest that WM inflammation occurs earlier than WM damage following abnormal Aβ accumulation in AD. The negative correlation between NII-derived cellular diffusivity and CSF Aβ42 level (a marker of amyloidosis) may indicate that WM inflammation is associated with increasing Aβ burden. NII-derived FA also negatively correlated with CSF t-tau level (a marker of neurodegeneration), suggesting that disruption of WM integrity is associated with increasing neurodegeneration. Our findings demonstrated the capability of NII to simultaneously image and quantify WM cellularity changes and damage in preclinical and early symptomatic AD. NII may serve as a clinically feasible imaging tool to study the individual and composite roles of WM inflammation and damage in AD. Keywords: Inflammation, White matter damage, Diffusion basis spectrum imaging, Neuro-inflammation imaging, Cerebrospinal fluid, Preclinical Alzheimer disease, Early symptomatic Alzheimer disease, Magnetic resonance imagin

Optimization of the diffusion-weighted MRI processing pipeline for the longitudinal assessment of the brain microstructure in a rat model of Alzheimer’s disease

Tese de mestrado integrado, Engenharia Biomédica e Biofísica (Radiações em Diagnóstico e Terapia) Universidade de Lisboa, Faculdade de Ciências, 2019The mechanism that triggers Alzheimer’s disease (AD) is not well-established, with amyloid plaques, neurofibrillary tangles of tau protein, microgliosis and glucose hypometabolism all likely involved in the early cascade. One main advantage of animal models is the possibility to tease out the impact of each insult on the neurodegeneration. Following an intracerebroventricular (icv) injection of streptozotocin (STZ), rats and monkeys develop impaired brain glucose metabolism, i.e. “diabetes of the brain”. Nu-merous studies have reported AD-like features in icv-STZ animals, but this model has never been char-acterized in terms of Magnetic Resonance Imaging (MRI)-derived biomarkers beyond structural brain atrophy. White matter degeneration has been proposed as a promising biomarker for AD that well pre-cedes cortical atrophy and correlates strongly with disease severity. Therefore, this project proposes a longitudinal study of white matter degeneration in icv-STZ rats using diffusion MRI. An existing image processing pipeline was primarily used to obtain preliminary results and propose an optimization strat-egy to improve it in terms of data quality and reliability. These strategies were tested and implemented in the pipeline when confirmed to be valuable, in order to achieve results as reproducible as possible and find the spatio-temporal pattern of brain degeneration in this animal model. All experiments were approved by the local Service for Veterinary Affairs. Male Wistar rats (N=18) (236±11 g) underwent a bilateral icv-injection of either streptozotocin (3 mg/kg, STZ group, N=10) or buffer (control group, CTL, N=8). Rats were scanned at four timepoints following surgery on a 14 T Varian system. Diffusion data were acquired using a semi-adiabatic SE-EPI PGSE sequence as follows: 4 (b=0 ms/μm2), 12 (b=0.8 ms/μm2), 16 (b=1.3 ms/μm2) and 30 (b=2 ms/μm2) directions; TE/TR=48/2500 ms, 9 coronal 1 mm slices, δ/Δ=4/27 ms, FOV=23x17 mm2, matrix=128x64 and 4 shots. The existing image processing pipeline included image denoising and eddy-correction. Moreover, diffusion and kurtosis tensors were calculated for each voxel, producing parametric maps of fractional anisotropy (FA), mean, axial and radial diffusivity (MD, AxD and RD) and mean, axial and radial kur-tosis (MK, AK and RK). Additionally, the two-compartment WMTI-Watson model was further esti-mated to provide specificity to the microstructure assessment. The following metrics were derived from the model: volume water fraction , parallel intra-axonal diffusivity , parallel ,║ and perpendicular extra-axonal diffusivities ,ꓕ and dispersion of fiber orientations 2. Since the model allows for two mathematical solutions, the >,║ solution was retained based on recent evidence. Considering pre-vious findings, the corpus callosum, cingulum, fornix and fimbria were chosen as white matter regions of interest (ROIs) and automatically segmented using anatomical atlas-based registration. Mean diffu-sion metrics were calculated in each ROI for each dataset. CTL and STZ groups were compared using two-sided t-tests at each timepoint. Within-group longitudinal changes were assessed using one-way ANOVA. Because of the small cohort, statistical analysis excluded the last time point. In the course of this project, strategies to optimize the existing pipeline were developed and tested. The existing brain atlas template was supplemented with white matter labels, rat brain extraction was semi-automated, and bias field correction of anatomical data was added before registration. Ventricle enlargement is typically reported in icv-STZ animals and normally constitutes an issue of misalignment in registration. In order to better match the label ROIs with the respective underlying tissue, several registration procedures were tested with different FA and color-coded FA template images. Color-coded FA-based registration dramatically improved the segmentation of the corpus callosum and the fimbria and reliability of diffusion metrics extracted from these regions. Moreover, additional fiber metrics were extracted from a newly developed tractography pipeline to compare with tensors metrics and finally, tensors metrics were evaluated in the gray matter for a more comprehensive spatio-temporal character-ization of brain degeneration. Results from statistical analysis were obtained after implementing the successful optimization strat-egies into the pipeline. There were few significant differences within groups over time. However, be-tween-group differences at each time point were more pronounced. White matter microstructure altera-tions were consistent with previous studies of histology and cognitive performance of the icv-STZ model. Changes in tensors metrics indicate early axonal injury in the fimbria and fornix at 2 weeks after injection, a period of potential recovery at 6 weeks after injection and late axonal injury at 13 weeks in all ROIs. The WMTI-Watson biophysical model provided specificity to the underlying microstructure, by showing intra-axonal damage in the fimbria and corpus callosum as early as 2 weeks, followed by a recover period and definite axonal loss at 13 weeks after injection. Results from tensors metrics and the WMTI-Watson model are not only complementary, they are consistent with each other and with previously-established trends for structural thickness, memory per-formance, amyloid deposition and inflammation. The icv-STZ model displays white matter changes in tracts reportedly affected by AD, while the degeneration is induced primarily by impaired brain glucose metabolism. The icv-STZ constitutes an excellent model to reproduce sporadic AD and should allow to further explore the hypothesis of AD being “type III diabetes”. The combination of diffusion information extracted from tensor imaging and biophysical modelling is a promising set of tools to assess white matter in the AD brain and might be the upcoming strategy to assess the human brain. Regarding future work, it will focus on estimating the correlation between microstructural alterations and functional con-nectivity (from resting-state functional MRI), glucose hypometabolism (from FDG-PET), and patholog-ical features (from histological stainings) – all currently under processing at CIBM. Tractography is a cutting-edge methodology to assess brain connectivity and the pipeline created could be further devel-oped to improve understanding and support diffusion metrics. The relationship between white and gray matter will also improve the understanding of spatio-temporal degeneration and the progression nature of the disease.O mecanismo que desencadeia a doença de Alzheimer (DA) não é bem conhecido, contudo sabe-se que a presença de placas amilóides e de emaranhados neurofibrilares da proteína tau, microgliose e ainda hipometabolismo de glucose estão envolvidos na fase inicial da cascata de desenvolvimento da doença. A principal vantagem dos modelos animais é justamente a possibilidade de estudar individualmente o impacto de cada um destes mecanismos no processo de neurodegeneração. Após uma injeção intracere-broventricular (icv) de estreptozotocina (STZ), várias espécies de animais mostraram um metabolismo anormal de glucose no cérebro, processo que foi referido como “diabetes do cérebro”. Vários estudos demonstraram que animais icv-STZ são portadores de características típicas de DA, mas este modelo animal nunca foi estudado em termos de biomarcadores derivados de técnicas de imagem por ressonân-cia magnética (IRM), exceto atrofia estrutural do cérebro. Um biomarcador promissor de DA que se acredita preceder a atrofia do córtex cerebral é a degeneração da matéria branca do cérebro, uma vez que foi fortemente correlacionado com a progressão e gravidade da doença. Logo, este projeto propõe um estudo longitudinal da degeneração da matéria branca em ratazanas icv-STZ utilizando IRM de di-fusão. O plano de processamento de imagem existente foi utilizado primeiramente para obter resultados preliminares e viabilizar a proposta de estratégias de otimização da mesma, em termos de melhoramento da qualidade de imagem e credibilidade das variáveis extraídas das imagens resultantes. Estas estratégias foram testadas e implementadas no plano de processamento quando a sua performance confirmou ser de valor, para que os resultados fossem o mais reproduzíveis possível em caracterizar a distribuição espácio-temporal da degeneração do cérebro neste modelo animal. Todos os procedimentos aqui descritos foram aprovados pelo serviço local dos assuntos veterinários. Ratazanas macho Wistar (N=18, 236±11 g) foram submetidas a uma injeção icv de STZ (3 mg/kg) no caso do grupo infetado (N=10) ou de um buffer no caso do grupo de controlo (N=8). As ratazanas foram examinadas no scanner de IRM do tipo Varian de 14 T em quatro momentos no tempo: 2, 6, 13 e 21 semanas após a injeção. As imagens por difusão foram adquiridas com uma sequência semi-adiabática spin-echo EPI PGSE com os seguintes parâmetros: 4 (b=0), 12 (b=0.8 ms/μm2), 16 (b=1.3 ms/μm2) and 30 (b=2 ms/μm2) direções; TE/TR=48/2500 ms, 9 secções coronais de 1 mm, δ/Δ=4/27 ms, FOV=23x17 mm2, matriz=128x64 e 4 shots. O plano existente de processamento de imagem incluía a correção das imagens ao nível de ruído e correntes-eddy. Posteriormente, os tensores de difusão e curtose foram estimados para cada voxel e os mapas paramétricos de anisotropia fracional (FA), difusão média, axial e radial (MD, AD e RD) e cur-tose média, axial e radial (MK, AK e RK) foram calculados. Adicionalmente, um modelo de difusão de água nas fibras da matéria branca foi utilizado para providenciar maior especificidade ao estudo da microestrutura do cérebro. Como tal, o modelo de dois compartimentos denominado WMTI-Watson foi também estimado e as seguintes variáveis foram derivadas do mesmo: a fração do volume de água , a difusividade paralela intra-axonal , as difusividades paralela ,║ e perpendicular ,ꓕ extra-axonais e, finalmente, a orientação da dispersão axonal 2. Este modelo matemático tem duas soluções possíveis dada a sua natureza quadrática, pelo que a solução >,║ foi imposta com base em evidências re-centes. Considerando estudos anteriores, as regiões de interesse (RDIs) da matéria branca escolhidas para analisar a microestrutura cerebral foram o corpo caloso, o cíngulo, a fimbria e a fórnix. Estes foram automaticamente segmentados através de registo de imagem de um atlas das regiões do cérebro da rata-zana e as médias das medidas extraídas dos tensores de difusão e curtose e ainda do modelo biofísico neuronal foram calculadas em cada RDI para cada conjunto de imagens obtidas. Os dois grupos de teste e controlo foram comparados usando testes t de Student bilaterais em cada momento do tempo, e a comparação das alterações longitudinais em cada grupo foi feita usando uma ANOVA. Devido ao baixo número de amostras, o último momento no tempo às 21 semanas foi excluído da análise. No decorrer deste projeto, várias estratégias para otimizar o processamento de imagem ou comple-mentar a análise da informação disponível foram testadas. Nomeadamente, o atlas cerebral da ratazana foi aperfeiçoado relativamente às regiões de matéria branca, a segmentação do cérebro foi testada com algoritmos automáticos e a correção do bias field em imagens estruturais de IRM foi adicionada ao plano antes do registo de imagem. O aumento dos ventrículos cerebrais é uma característica frequente em animais icv-STZ, constituindo um problema de alinhamento nos métodos de registo de imagem. No sentido de otimizar a correspondência entre as regiões do atlas e as respetivas regiões na imagem estru-tural e por difusão, vários procedimentos de registo de imagem foram testados. O co-registo de imagem convencional utiliza imagens estruturais para normalizar o espaço das imagens por difusão, no entanto os mapas paramétricos de FA têm vindo a substituir este conceito dado o excelente contraste que provi-denciam entre a matéria branca e cinzenta do cérebro. Mapas de FA com diferentes direções predomi-nantes mostraram uma melhoria significante da segmentação do corpo caloso e da fimbria e também do poder estatístico das variáveis extraídas destas RDIs. Adicionalmente, um novo plano de processamento de tratografia foi construído de raiz no âmbito deste projeto para extrair variáveis adicionais das fibras de interesse e compará-las com as variáveis de difusão obtidas por análise voxel-a-voxel. Por último, as variáveis calculadas através dos tensores de difusão e curtose foram avaliadas na matéria cinzenta do cérebro para uma caracterização espácio-temporal da degeneração cerebral na DA. Os resultados da análise estatística foram obtidos após integrar no plano de processamento as estra-tégias que mostraram valorizar o projeto em termos de qualidade de imagem ou credibilidade das vari-áveis. Houve poucas diferenças significativas ao longo do tempo em cada grupo, no entanto as diferen-ças entre grupos foram bastante acentuadas. As alterações ao nível da microestrutura da matéria branca foram consistentes com estudos prévios em animais icv-STZ usando métodos histológicos e avaliações das suas capacidades cognitivas. Alterações nas variáveis extraídas dos tensores indicaram deficiência axonal inicial na fimbria e no fórnix 2 semanas após injeção no grupo de teste, um potencial período de recuperação às 6 semanas e novamente deficiência axonal às 13 semanas, sendo que neste período tardio todas as RDIs foram afetadas. O modelo biofísico WMTI-Watson confirmou aumentar especificidade ao estudo da microestrutura, visto que demostrou danos intra-axonais na fimbria e no corpo caloso 2 semanas após injeção, seguidos de um período de recuperação e de perda de estrutura axonal definitiva às 13 semanas em todas as RDIs. Não só estes dois métodos de análise de IRM de difusão se complementam, como são também con-sistentes entre eles e com as tendências de alterações ao longo do tempo descritas noutros estudos. Além disso, o animal icv-STZ mostrou alterações características da DA, mesmo tendo a degeneração cerebral sido induzida pela disrupção do metabolismo de glucose no cérebro. Como tal, este modelo animal é excelente para reproduzir a doença e deverá continuar a ser avaliado nas diferentes áreas multidiscipli-nares para explorar a hipótese de a DA ser desencadeada pela falha do sistema insulina/glucose. A com-binação da informação de difusão obtida dos tensores e da modelação da difusão neuronal provou ser uma ferramenta promissora no estudo das fibras da matéria branca do cérebro e poderá vir a ser o desafio futuro no que toca a investigação clínica da DA. Este estudo focar-se-á em correlacionar as alterações microestruturais aqui descritas com dados de conectividade funcional (obtida por IRM funcional em repouso), hipometabolismo de glucose (por FDG-PET) e outras características patológicas (por colora-ção histológica) – todos já em curso no CIBM. Tratografia é a metodologia topo de gama para aceder à conetividade cerebral e o plano de processamento gerado neste projeto poderá continuar a ser desenvol-vido no futuro para informação adicional, assim como a relação entre a matéria branca e cinzenta poderá suplementar a compreensão da progressão da doença no espaço e no tempo

Influence of Analysis Technique on Measurement of Diffusion Tensor Imaging Parameters

We compared results from various methods of analysis of diffusion tensor imaging (DTI) data from a single data set consisting of 10 healthy adolescents

Applications of NODDI for imaging in vivo white matter pathology in neurodegenerative diseases

This thesis aims to evaluate: 1) the feasibility of advanced diffusion Magnetic Resonance Imaging (MRI) technique − Neurite orientation dispersion and density imaging (NODDI) for providing in vivo imaging evidence of white matter (WM) pathology at both preclinical and clinical stages of neurodegenerative diseases; 2) the added value of this advanced technique - NODDI over the standard diffusion MRI technique - Diffusion Tensor Imaging (DTI). Monitoring WM pathology is vital in coping with this challenge brought by neurodegenerative diseases as abnormal axonal transport has been identified in neurodegenerative diseases. In vivo imaging evidence using DTI suggests that patients with neurodegenerative diseases have abnormal WM microstructure compared to normal controls. Whilst sensitive, DTI metrics lack tissue specificity to biological features due to the simplicity of the model, therefore could not inform more on the disease pathology. In contrast, NODDI could provide biologically meaningful metrics that have been validated with histological measures in human neural tissue. Therefore, investigating the potential of NODDI in clinical studies of neurodegenerative diseases could greatly increase our knowledge and benefit our understanding of the disease pathology. In this thesis, we chose pre-manifest Huntington's disease and young onset Alzheimer's disease as the disease models to represent the preclinical and clinical stages respectively. We demonstrated the feasibility of NODDI in not only detecting WM abnormalities at both preclinical and clinical stages of neurodegenerative diseases but also tracking the longitudinal progression of WM microstructural deficits at the clinical stage. We also demonstrated the clinical relevance of NODDI by evaluating the correlations between the clinical assessments and NODDI metrics. Compared with DTI, we found that NODDI could provide more information on disease-specific WM pathology

Group-level progressive alterations in brain connectivity patterns revealed by diffusion-tensor brain networks across severity stages in Alzheimer's disease

Alzheimer’s disease (AD) is a chronically progressive neurodegenerative disease highly correlated to aging. Whether AD originates by targeting a localized brain area and propagates to the rest of the brain across disease-severity progression is a question with an unknown answer. Here, we aim to provide an answer to this question at the group-level by looking at differences in diffusion-tensor brain networks. In particular, making use of data from Alzheimer’s Disease Neuroimaging Initiative (ADNI), four different groups were defined (all of them matched by age, sex and education level): G1 (N1 = 36, healthy control subjects, Control), G2 (N2 = 36, early mild cognitive impairment, EMCI), G3 (N3 = 36, late mild cognitive impairment, LMCI) and G4 (N4 = 36, AD). Diffusion-tensor brain networks were compared across three disease stages: stage I (Control vs. EMCI), stage II (Control vs. LMCI) and stage III (Control vs. AD). The group comparison was performed using the multivariate distance matrix regression analysis, a technique that was born in genomics and was recently proposed to handle brain functional networks, but here applied to diffusion-tensor data. The results were threefold: First, no significant differences were found in stage I. Second, significant differences were found in stage II in the connectivity pattern of a subnetwork strongly associated to memory function (including part of the hippocampus, amygdala, entorhinal cortex, fusiform gyrus, inferior and middle temporal gyrus, parahippocampal gyrus and temporal pole). Third, a widespread disconnection across the entire AD brain was found in stage III, affecting more strongly the same memory subnetwork appearing in stage II, plus the other new subnetworks, including the default mode network, medial visual network, frontoparietal regions and striatum. Our results are consistent with a scenario where progressive alterations of connectivity arise as the disease severity increases and provide the brain areas possibly involved in such a degenerative process. Further studies applying the same strategy to longitudinal data are needed to fully confirm this scenario

Imaging changes associated with cognitive abnormalities in Parkinson's disease

The current study investigates both gray and white matter changes in non-demented Parkinson's disease (PD) patients with varying degrees of mild cognitive deficits and elucidates the relationships between the structural changes and clinical sequelae of PD. Twenty-six PD patients and 15 healthy controls (HCs) were enrolled in the study. Participants underwent T1-weighted and diffusion tensor imaging (DTI) scans. Their cognition was assessed using a neuropsychological battery. Compared with HCs, PD patients showed significant cortical thinning in sensorimotor (left pre- and postcentral gyri) and cognitive (left dorsolateral superior frontal gyrus [DLSFG]) regions. The DLSFG cortical thinning correlated with executive and global cognitive impairment in PD patients. PD patients showed white matter abnormalities as well, primarily in bilateral frontal and temporal regions, which also correlated with executive and global cognitive impairment. These results seem to suggest that both gray and white matter changes in the frontal regions may constitute an early pathological substrate of cognitive impairment of PD providing a sensitive biomarker for brain changes in PD

Widespread Structural and Functional Connectivity Changes in Amyotrophic Lateral Sclerosis: Insights from Advanced Neuroimaging Research

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease principally affecting motor neurons. Besides motor symptoms, a subset of patients develop cognitive disturbances or even frontotemporal dementia (FTD), indicating that ALS may also involve extramotor brain regions. Both neuropathological and neuroimaging findings have provided further insight on the widespread effect of the neurodegeneration on brain connectivity and the underlying neurobiology of motor neurons degeneration. However, associated effects on motor and extramotor brain networks are largely unknown. Particularly, neuropathological findings suggest that ALS not only affects the frontotemporal network but rather is part of a wide clinicopathological spectrum of brain disorders known as TAR-DNA binding protein 43 (TDP-43) proteinopathies. This paper reviews the current state of knowledge concerning the neuropsychological and neuropathological sequelae of TDP-43 proteinopathies, with special focus on the neuroimaging findings associated with cognitive change in ALS

The Associations Between Football Exposure, Concussion History and Playing Position on Cerebral White Matter Integrity and Neurocognitive Performance

Diffusion tensor imaging (DTI) has emerged as an important tool for quantitative analysis of white matter (WM) integrity following sport-related concussions. The purpose of this research was to investigate the variances in WM integrity (defined by fractional anisotropy (FA) and medial diffusivity (MD)) and neurocognitive performances in retired college and professional football athletes based on concussion history, duration of playing career, and playing position. MRI scans and neurocognitive test scores from 32 former college and 31 former age-matched professional players (avg age=58.5 SD=3.7) were compared. A permuted, voxel-wise 3x2 ANOVA was performed on the WM skeleton to investigate the main and interaction effects on WM integrity. Threshold-free cluster enhancement (TFCE) was used to identify clusters of significantly different FA or MD and post-hoc univariate analyses were used to determine the direction of interaction effects. A priori alpha level was set at 0.05 after correction for multiple comparisons. Differences in FA were observed in 3 clusters in the forceps minor and genu of the corpus callosum for the concussion by position interaction. Post-hoc analysis of the peak voxels within each cluster revealed consistently lower FA in non-speed athletes with 3+ concussions as compared to those with 01 concussions (Cohen’s d: 0.89, 0.95, and 1.29; P<0.05). No clear differences in neurocognitive abilities were identified. Our results suggest a history of multiple concussions is associated with lower FA in former non-speed position players compared to speed players, particularly in frontal white matter tracts. We did not observe main effects of football exposure, suggesting that without concussive injuries, added football exposure does not account for variances in white matter integrity and neurocognitive abilities. A limitation of these results is the lack of a control group without history of football participationBachelor of Art

THE DEFAULT MODE NETWORK AND EXECUTIVE FUNCTION: INFLUENCE OF AGE, WHITE MATTER CONNECTIVITY, AND ALZHEIMER’S PATHOLOGY

The default mode network (DMN) consists of a set of interconnected brain regions supporting autobiographical memory, our concept of the self, and the internal monologue. These processes must be maintained at all times and consume the highest amount of the brain’s energy during its baseline state. However, when faced with an active, externally-directed cognitive task, the DMN shows a small, but significant, decrease in activity. The reduction in DMN activity during the performance of an active, externally-directed task compared to a baseline state is termed task-induced deactivation (TID), which is thought to ‘free-up’ resources required to respond to external demands. However, older adults show a reduced level of TID in the DMN. Recently, it has begun to be appreciated that this decrease in TID may be associated with poorer cognitive performance, especially during tasks placing high demands on executive function (EF). Diminished DMN TID has not only been associated with increasing age but also with multiple age-related neurobiological correlates such as accumulating Alzheimer’s disease (AD) pathology and reductions in white matter (WM) connectivity. However, these biological factors—age, WM connectivity reductions and increasing AD pathology—are themselves related. Based on the literature, we hypothesized that declining WM connectivity may represent a common pathway by which both age and AD pathology contribute to diminished DMN TID. Further, we hypothesized that declines in DMN function and WM connectivity would predict poorer in EF. Three experiments were carried out to test these hypotheses. Experiment 1 tested whether WM connectivity predicted the level of DMN TID during a task requiring a high level of EF. Results from 117 adults (ages 25-83) showed that WM connectivity declined with increasing age, and that this decline in WM connectivity was directly associated with reduced DMN TID during the task. Experiment 2 tested whether declines in WM connectivity explained both age-related and AD pathology-related declines in DMN TID. Results from 29 younger adults and 35 older adults showed that declining WM connectivity was associated with increasing age and AD pathology, and that this decline in WM connectivity was a common pathway for diminished DMN TID associated with either aging or AD pathology. Experiment 3 investigated whether measures of WM connectivity and DMN TID at baseline could predict EF measured using clinically-used tests. Results from 29 older adults from Experiment 2 showed that less DMN TID predicted poorer EF at baseline and diminished WM connectivity at baseline predicted a greater decline in EF after 3 years. Further, WM connectivity explained reductions in EF predicted by baseline AD pathology, as well as further reductions in EF not predicted by baseline AD pathology. Together the results of these studies suggest that WM connectivity is a key pathway for age-related and AD pathology-related patterns of diminished DMN TID associated with poorer EF. Further, WM connectivity may represent a potential therapeutic target for interventions attempting to prevent future declines in EF occurring in aging and AD

Dysfonctions cérébrales et changements neuroanatomiques dans l’apnée obstructive du sommeil chez les personnes âgées

L’apnée obstructive du sommeil (AOS) est un trouble du sommeil particulièrement prévalent dans la population âgée, qui peut se présenter par différents niveaux de sévérité. Des études épidémiologiques récentes ont montré une association entre l’AOS et l’incidence de la démence. De plus, l’AOS a été identifiée de façon répétée comme un facteur de risque d’accident vasculaire cérébral. Ces conséquences potentielles de l’AOS sur le cerveau pourraient être dues à l’hypoxémie intermittente et à la fragmentation du sommeil causées par les obstructions respiratoires répétées. Bien que l’AOS soit impliquée dans l’incidence de conséquences graves sur le cerveau, son impact sur la fonction et la structure du cerveau vieillissant reste sous-évalué. Ainsi, l’objectif de cette thèse est d’évaluer l’association entre l’AOS et sa sévérité sur le fonctionnement cérébral et la structure neuroanatomique chez des personnes âgées de plus de 55 ans. Nous avons émis l’hypothèse que les changements cérébraux chez les personnes avec AOS pourraient s’apparenter aux profils observés dans les stades précurseurs de déclin cognitif. Pour ce faire, diverses méthodes de neuroimagerie ont été utilisées pour caractériser l’ensemble du cerveau des personnes avec AOS. Le fonctionnement cérébral au repos éveillé a été évalué par le biais de la tomographie par émission monophotonique en mesurant le flot sanguin cérébral régional. La structure anatomique de la matière grise et de la matière blanche a été évaluée en imagerie par résonance magnétique. La structure de la matière grise a été évaluée grâce à diverses techniques structurelles, mesurant le volume de la matière grise et l’épaisseur corticale. La structure de la matière blanche a été évaluée avec des méthodes d’imagerie de diffusion, mesurant la diffusivité des molécules d’eau dans la matière blanche. Dans notre premier article, nous observons que l’AOS sévère, ainsi que plusieurs marqueurs de sévérité de l’AOS sont associés avec des régions d’hypoperfusion au repos éveillé. Ces réductions régionales de la perfusion cérébrales pourraient être dues à un moins bon fonctionnement des neurones et cellules gliales. Dans notre deuxième article, nous montrons que le profil régional d’hypoperfusion cérébrale diurne diffère selon que l’AOS soit observée en sommeil paradoxal ou en sommeil lent. Chez des personnes avec une sévérité plus faible d’AOS, la présence d’évènements respiratoires en sommeil paradoxal était tout de même associée avec une réduction de la perfusion cérébrale. Ceci suggère que les évènements respiratoires en sommeil paradoxal pourraient être plus dommageables pour le cerveau que ceux en sommeil lent. Nos résultats suggèrent que l’AOS entraine une réduction du fonctionnement cérébral mesuré par une réduction régionale de la perfusion cérébrale. De plus, ces articles suggèrent également que plusieurs facteurs dans l’AOS contribuent différemment aux dysfonctions cérébrales. Dans notre troisième article, nous observons que les perturbations respiratoires, la fragmentation du sommeil, mais surtout l’hypoxémie contribuent à l’hypertrophie de la matière grise. Nous suggérons qu’un processus d’œdème, ou d’autres processus réactifs et aigus pourraient être en cause dans l’augmentation de la taille de la matière grise. Ce processus pourrait également expliquer nos résultats du dernier article. Dans notre quatrième et dernier article, nous montrons que l’AOS est associée avec une réduction de la diffusivité des molécules d’eau dans la matière blanche, surtout dans les cas légers d’AOS. Un processus d’œdème intracellulaire pourrait restreindre la diffusivité des molécules d’eau dans les cellules de la matière blanche. Les résultats de cette thèse clarifient les changements cérébraux observés dans la population vieillissante avec l’AOS. Ainsi, malgré des réductions de la perfusion cérébrale suggérant un dysfonctionnement cérébral, l’AOS est également associée avec des changements de structure de la matière grise et de la matière blanche suggérant des processus réactifs et aigus. Puisque ce profil a été rapporté dans les stades précurseurs de déclin cognitif et de démence, nos résultats soulèvent l’importance d’identifier les facteurs dans l’AOS qui sont associés avec les changements cérébraux, afin d’identifier les individus à risque de conséquences cérébrales négatives. De plus, nos résultats soulèvent également l’importance d’évaluer les effets du traitement de l’AOS pour éviter ou ralentir les conséquences de celle-ci sur la santé cérébrale et cognitive.Obstructive sleep apnea (OSA) is a sleep disorder especially common in the older population, which can present itself at different levels of severity. Recent epidemiological studies showed an association between OSA and incident dementia. In addition, AOS was repeatedly identified as a risk factor for stroke. These potential consequences of OSA on the brain could be caused by intermittent hypoxemia and sleep fragmentation, which is observed following repeated respiratory obstructions. Although OSA has been implicated in the incidence of serious consequences on brain health, its impact on the function and structure of the aging brain remains unclear. Thus, the objective of this thesis was to evaluate the association between OSA as well as its severity with cerebral functioning and structure in adults aged 55 years old and over. We hypothesized that cerebral changes in individuals with OSA would be similar to profiles observed in preclinical stages of cognitive decline. In order to achieve this goal, various neuroimaging methods were used to characterize the brain of individuals with OSA as a whole. Cerebral functioning during wakeful rest was evaluated with single-photon emission computed tomography by measuring regional cerebral blood flow. Grey matter and white matter structure were evaluated with magnetic resonance imaging. Grey matter structure was assessed with structural techniques that measure grey matter volume and cortical thickness. White matter was assessed with diffusion tensor imaging that measures water molecules diffusion. In our first study, we observed that severe OSA as well as many markers associated with OSA severity were correlated with hypoperfused regions during wakeful rest. These regions of reduced cerebral perfusion could present altered neuronal and glial functioning. In our second study, we showed that the daytime regional pattern of cerebral hypoperfusion was different whether apneas and hypopneas were observed during rapid eye movement sleep or non-rapid eye movement sleep. In individuals with a milder OSA severity, respiratory events during rapid eye movement sleep were still associated with regions of hypoperfusion. This suggests that respiratory events during rapid eye movement sleep may be more detrimental to brain health than those in non-rapid eye movement sleep. Overall, these results suggest that OSA leads to an altered cerebral functioning as evidenced by decreased regional cerebral perfusion. In addition, these studies also suggest that many factors contribute differently to cerebral dysfunction in OSA. In our third study, we observed that respiratory disturbances, sleep fragmentation, and mostly hypoxemia all contributed to grey matter hypertrophy. We suggest that oedema or other reactive or acute processes could cause these increased in grey matter structure. These processes may also explain our results observed in our last study. In that fourth study, we showed that OSA is associated with reduced white matter diffusivities, especially in milder OSA cases. An intracellular oedema process may restrict the diffusion of water molecules inside cells. The results of this thesis clarify the cerebral changes observed in the aging population with OSA. Although reduced regional brain perfusion suggests cerebral dysfunctions, OSA was also associated with grey and white matter structural changes that suggest reactive and acute processes. Because this pattern was reported previously in preclinical stages of cognitive decline and dementia, our results highlight the importance of identifying individuals at higher risk of negative outcomes to brain health. In addition, our results also emphasize the importance of understanding the efficiency of treating OSA in order to prevent or slow its impact on cerebral functioning and structure