In this study, the brain of senescence accelerated mouse prone 8 (SAMP8) mice model was adopted to investigate PTMs state (especially methylation patterns) of core histones (H2A, H2B, H3 and H4). Seven methylated sites (H3K24, H3K27, H3K36, H3K79, H3R128, H4K20 and H2A R89) were detected by tandem matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF MS) analysis. The methylation of H3K27 and H3K36 demonstrated a modulating relationship and methylated H3K27 might contribute to the hypermethylation state and gene repression in aged brain. Western blotting results showed that mono-methylated H4K20 decreased during SAMP8 mice aging and di-methylated H3K79 decreased in the brain of 12-month-old SAMP8 mice compared with age-matched senescence accelerated-resistant mouse (SAMR1) control. Di-methylated H3K79 could express in neuron cells of cerebral cortex and hippocampus. Whereas, the number of H3K79 methylation negative cells was higher in the cortex of 12-month old SAMP8 mice than that of age-matched control SAMR1 mice. Chromatin immunoprecipitation (ChIP) result indicated homeodomain transcription factor Pbx1 isoform 1 (Pbx1), transcription factors and transcriptional regulator proteins, such as T-box isoform 20, TetR family precursor BAZ2B and ribosomal protein, were recruited to methylated H3K79 site. Therefore, a model of methylated H3K79 on gene transcriptional regulation was proposed. Furthermore, the consequences of decreased H3K79 methylation in Neuro-2a (N2a) cells were investigated via transfection with Dot1 (disruptor of telomeric silencing) siRNA. After transfection, N2a cells displayed shorter neurite and less dendrite. Proteomic change in the N2a cells provided convincing evidence for the multi-function of decreased H3K79 methylation on transcriptional regulation, protein translation and folding, stress response and DNA breaks repair, which would contribute to brain dysfunction during neurodegenerative disease or aging. / Nowadays, many countries including China are experiencing aging populations. Aging has become the major risk factor for many diseases, such as neurodegenerative disease. The studies on the role of epigenetics in the aging process have grown tremendously in recent years. However, no systematic investigations have provided the information on histone post-translational modifications (PTMs) in aged brain and the roles of histone PTMs in brain aging are still unknown. / This study gave a new insight into the link between histone PTMs and brain aging. It could provide the experimental evidence for future studies and help us to better understand aging or neurodegenerative disease at epigenetic level. Furthermore, it could benefit for setting up the strategies for epigenetic therapy to neurodegenerative disease. / Wang, Chunmei. / Adviser: Ngai Saiming. / Source: Dissertation Abstracts International, Volume: 73-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaf 136). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

O processo de envelhecimento é acompanhado por um declínio nas funções cognitivas, principalmente, de funções fluidas ou de processamento. Essas diminuições são pelo menos, em parte, devido a alterações estruturais e funcionais do sistema nervoso central. Uma abordagem para estudar as mudanças funcionais é a medição da utilização metabólica regional da glicose, ou, alternativamente, um parâmetro físico correlacionado ao metabolismo cerebral e à atividade funcional local, como o fluxo sanguíneo cerebral (CBF). Neste contexto, em Imagens por Ressonância Magnética (IRM), a técnica de Marcação dos Spins Arteriais (ASL) surge como uma importante ferramenta não invasiva para análises perfusionais. Seu uso não só permite avaliar a perfusão sanguínea cerebral, gerando mapas quantitativos de CBF, mas também fornecer uma alternativa para estudar a conectividade funcional (FC), um parâmetro importante para descrição da topologia e funcionalidade cerebral. Sessenta e três indivíduos saudáveis, na faixa etária entre dezoito à setenta e dois anos, foram recrutados para participar deste estudo. Análises estatísticas mostram uma diminuição de CBF em várias regiões cerebrais, especialmente nos lobos frontal e temporal, que acompanham o processo de envelhecimento. As medidas de FC foram obtidas em análises por regiões de interesse e teoria de grafos; estas também demostraram uma diminuição, com o avanço da idade, em regiões presentes nos lobos frontal e temporal, mas também relataram um maior número de regiões prejudicadas no lobo parietal. Portanto, usando uma técnica de imagem não invasiva, foi possível observar déficits de CBF além de alterações de aspectos da organização funcional, oferecendo valores quantitativos que podem ajudar na melhor descrição dos efeitos do envelhecimento na hemodinâmica cerebral. / Aging process is accompanied by a decline in cognitive functions foremost comprise fluid or processing-based functions. These decreases are at least partly due to structural and functional deteriorating changes of the central nervous system. One approach to study these functional changes is the measurement of the regional metabolic utilization of glucose, or, alternatively, a physical quantity correlated to cerebral metabolism and local functional activity, such as the cerebral blood flow (CBF). In this context, Arterial spin labeling (ASL) emerges as a noninvasive Magnetic Resonance Imaging (MRI) perfusion technique. Its use not only allows assessing cerebral perfusion, by generating CBF values, but also can provide an alternative to study functional connectivity (FC), which is an important parameter that describes the brain topology and functionality. Sixty-three healthy subjects, from age eighteen to seventy-two years, were recruited to participate in this study. ASL-CBF maps showed a decrease in several brain regions, especially in frontal and temporal lobes that follows aging process. FC measures were assessed with regions of interest (ROI-to-ROI) and graph theory analysis, also showing a decrease in regions present in frontal and temporal lobes, and also more impaired regions in the parietal lobe. Therefore, using a noninvasive imaging technique it was possible to observe CBF deficits besides alteration in aspects on functional organization, offering quantitative values that can help to describe better the aging effects on cerebral hemodynamics.

Actuellement, l’étude du mouvement des tissus biologiques figure parmi les thématiques majeures dans le domaine de l’imagerie médicale, dont le challenge est d’apporter un complément d’information clinique et de permettre une aide au diagnostic. L’application récente de techniques d’élastographie ouvre de nouvelles perspectives de caractérisation biomécanique des tissus, et notamment du cerveau. Dans ce contexte, nous proposons une méthodologie innovante d’élastographie passive des propriétés mécaniques du tissu cérébral dont le but est de permettre à terme le diagnostic des maladies neurodégénératives. / The study of biological tissues movement is currently, one of the major thematics in the medical imaging field. The challenge is to provide additional clinical information and allow for diagnostic assistance. The recently introduced elastographic techniques, provide ample opportunities for biomechanical tissues characterization, particularly of cerebral tissues. An innovative passive-elastographic methodology for assessing mechanical properties of brain tissue is proposed. The eventual aim is to allow for the diagnosis of neurodegenerative diseases.

Alzheimer´s Disease (AD) is the most prevalent cause of dementia, signifying a progressive and degenerative brain disorder that causes cognitive function deterioration including memory loss, communication difficulties, impaired judgment, and changes in behavior and personality. Compared to normal aging, AD introduces more profound cognitive impairments and brain morphology changes. Understanding these morphological changes associated with both normal aging and AD holds pivotal significance for the study of brain health. In recent years, the flourishing development of Artificial Intelligence (AI) has facilitated the analysis of medical images and the study of longitudinal brain morphology evolution. Numerous advanced AI-based frameworks have emerged to generate unbiased and realistic medical templates that represent the common characteristics within a cohort, providing valuable insights for cohort studies. Among these, Atlas-GAN is a state-of-the-art framework which can generate high-quality conditional deformable templates using diffeomorphic registration. However, cohort studies are not sufficient for individualized healthcare and treatment as each patient has a unique condition. Fortunately, the introduction of a mathematical mechanism, parallel transport, enables the inference of individual brain morphological evolution from cohort-level longitudinal templates. This project proposed an image generator that integrates the pole ladder, a tool for parallel transport implementation, into Atlas-GAN, to translate the cohort-level brain morphological evolution onto individual subjects, enabling the synthesis of anatomically plausible and personalized longitudinal Magnetic Resonance (MR) images based on one individual Magnetic Resonance Imaging (MRI) scan. In clinics, the synthesized images empower the physicians to retrospectively understand the patient's premorbid brain states and prospectively predict their brain morphology changes over time. Such capabilities are of paramount importance for the prognosis, diagnosis, and early-stage intervention of AD, especially given the current absence of a cure for AD. The primary contributions of this project include: (1) Introduction of an image generator that combines parallel transport with Atlas-GAN to synthesize individual longitudinal MR images for both the normal aging cohort and the cohort suffering from AD with both anatomical plausibility and preservation of individualized characteristics; (2) exploration into the prediction of individual longitudinal MR images in the case of an individual undergoing a state transition using the proposed generator; (3) conduction of both qualitative and quantitative evaluations and analyses for the synthesized images. / AD är den mest framträdande orsaken till demens och innebär en progressiv och degenerativ hjärnsjukdom som resulterar i kognitiv försämring, inklusive minnesförlust, kommunikationssvårigheter, nedsatt omdöme samt förändringar i beteende och personlighet. I jämförelse med normal åldrande introducerar AD mer djupgående kognitiva störningar och förändringar i hjärnans morfologi. Att förstå dessa morfologiska förändringar i samband med både normalt åldrande och AD har avgörande betydelse för studien av järnhälsa. De senaste årens blomstrande utveckling inom AI har underlättat analysen av medicinska bilder och studiet av långsiktig hjärnmorfologi. Flera avancerade AI-baserade ramverk har utvecklats för att generera opartiska och realistiska medicinska mallar som representerar gemensamma egenskaper inom en kohort och ger värdefulla insikter for kohortstudier. Bland dessa ar Atlas-GAN ett framstående ramverk som kan generera högkvalitativa, konditionellt deformabla mallar med hjälp av diffeomorfisk registrering. Dock ar kohortstudier inte tillräckliga för individualiserad sjukvård och behandling, eftersom varje patient har en unik situation. Som tur är möjliggör introduktionen av en matematisk mekanism, parallell transport, att man kan dra slutsatser om individuell hjärnmorfologisk utveckling från kohortbaserade longitudinella mallar. I detta projekt föreslogs en bildgenerator som integrerar pole ladder", ett verktyg for implementering av parallell transport, i Atlas- GAN. Detta möjliggör att kohortbaserad hjärnmorfologisk utveckling kan översättas till individnivå, vilket gör det möjligt att syntetisera anatomiskt trovärdiga och personifierade longitudinella MR-bilder baserade på en individs MRI-skanning. Inom kliniken gör de syntetiserade bilderna det möjligt för läkare att retrospektivt förstå patientens premorbida hjärnstatus och prospektivt förutsäga deras hjärnmorfologiska förändringar över tiden. Sådana möjligheter är av avgörande betydelse för prognos, diagnos och tidig intervention vid AD, särskilt med tanke på den nuvarande bristen på en botemedel för AD. De huvudsakliga bidragen från detta projekt inkluderar: (1) Introduktion av en bildgenerator som kombinerar parallell transport med Atlas-GAN för att syntetisera individuella longitudinella MR-bilder för både kohorten med normalt åldrande och kohorten som lider av AD, med både anatomisk trovärdighet och bevarande av individualiserade egenskaper. Dessutom har de genererade bilderna genomgått både kvalitativa och kvantitativa utvärderingar och analyser; (2) Utforskning av förutsägelse av individuella longitudinella MR-bilder i fallet när en individ genomgår en tillståndsövergång med hjälp av det föreslagna generatorn.

T1rho弛豫是旋轉坐標系中的自旋晶格弛豫，它決定橫向磁化向量在存有自旋鎖定射頻脈衝情況下的衰減，自旋鎖定脈衝與橫向磁化向量同向。T1rho磁共振成像對於低頻運動過程敏感，故可研究水與其周大分子物質環境間的交互作用，有鑒別組織內早期生化改變的潛力。 / 衰老與慢性高血壓是常見腦退行性疾病的兩個主要危險因素。但是正常腦衰老過程及慢性高血壓兩個因素與腦組織T1rho是否有相關性，尚缺乏研究。序貫性測量SD老鼠自5至15月齡、WKY（血壓正常）和SHR（患有自發性高血壓）老鼠自6至12月齡的雙側丘腦、海馬、和皮質的腦組織T1rho值。發現三組老鼠的丘腦、海馬及皮質的T1rho均隨年齡增長而增高；且SHR的顯著高於WKY老鼠。 / T1rho值與椎間盤退變等級的相關性已有報導。但相比T2值，T1rho在評價椎間盤退變方面是否優於或如何優於T2值尚缺乏研究。將椎間盤髓核及纖維環的T1rho和T2值與5級和8級椎間盤退變等級系統做比較；發現髓核的T1rho及T2與椎間盤退變等級的相關性均呈二次函數降低，且無顯著差別(P=0.40)。纖維環的T1rho及T2與椎間盤退變等級的相關性呈線性函數降低，T2降低的斜率明顯比T1rho降低的斜率要平坦(P<0.001)。故T1rho值比T2值更加適合評價纖維環退變，而兩者在評價髓核時相似。 / 肝纖維化是幾乎所有慢性肝病的常見特徵，包括大分子物質在細胞外基質的沉積。選用四氯化碳CCl4腹腔注射6周來製造肝纖維化模型。肝臟T1rho在注射後的第二天輕度上升，然後持續上升，直到注射六周後T1rho達最高值，此後T1rho隨CCl4注射停止而降低。顯示T1rho磁共振成像對於監測慢性注射CCl4誘導的肝纖維化及肝損傷有價值。當沒有明顯肝纖維化時，肝T1rho輕微受水腫及急性炎症的影響。 / 為將肝臟T1rho磁共振成像轉化到臨床使用，我們研究了其可行性，以及正常志願者肝臟T1rho值分佈範圍。發現採用六個自旋鎖定時間來測量健康志願者肝T1rho，結果有較高的可重複性和一致性，肝T1rho平均值為42.5ms，分佈範圍為38.8到46.5ms。採用三個自鎖鎖定時間點掃描，可以減少一半掃描時間，且可以得到可信的肝T1rho值，但採用兩個自旋鎖定時間點則不行。 / T1rho relaxation is spin-lattice relaxation in the rotating frame. It determines the decay of the transverse magnetization in the presence of a spin-lock radiofrequency pulse, which applied along the transverse magnetization. T1rho MRI is sensitive to low frequency motional processes, so it can be used to investigate the interaction between water molecules and their macromolecular environment. T1rho imaging is suggested to have the potential to identify early biochemical changes in tissues. / Aging and chronic hypertension are two major risk factors for common neurodegenerative disease. However, whether normal brain aging and chronic spontaneous hypertensive are associated with brain T1rho values changes were not reported. We longitudinally measured the T1rho value in rat brain of Sprague-Dawley (SD) rats from 5-month to 15-month, and spontaneous hypertensive rats (SHR) with Wistar Kyoto (WKY) rats from 6-month to 12-month. The T1rho values in three brain regions of thalamus, hippocampus, and cortices increased with aging process, and were significantly higher in SHR than WKY rats. / For intervertebral disc, the correlation between T1rho and degenerative grade has been reported. However, whether and how T1rho specifically offer better evaluation of disc degeneration compared with T2 was not studied previously. T1rho and T2 value of nucleus pulposus (NP) and annulus fibrosus (AF) was compared with reference to the five-level and eight-level semi-quantitative disc degeneration grading systems. For NP, T1rho and T2 decreased quadratically with disc degeneration grades and had no significant trend difference (P=0.40). In NP, T1rho and T2 decrease in a similar pattern following disc degeneration. For AF, T1rho and T2 decreased linearly and the slopes of T2 were significantly flatter than those of T1rho (P<0.001). Therefore, the T1rho is better suited for evaluating AF in degenerated disc than T2. / Liver fibrosis, a common feature of almost all causes of chronic liver disease, involves macromolecules accumulated within the extracellular matrix. Male Sprague-Dawley rats received intraperitoneal injection of 2 ml/kg CCl4 twice weekly for up to 6 weeks. Then CCl4 was withdrawn for recovery. The liver T1rho values increased slightly on day 2, then increased further and were highest at week 6 post CCl4 insults, and decreased upon the withdrawal of the CCl4 insult. This study demonstrated that T1rho MRI is a valuable imaging biomarker for liver injury and fibrosis induced by CCl4. Liver T1rho value was only mildly affected by edema and acute inflammation when there was no apparent fibrosis. / To translate liver T1rho MRI to clinical application, the technical feasibility of T1rho MRI in human liver was explored and the normal range of T1rho values in healthy volunteers was determined. We found it is feasible to obtain consistent liver T1rho measurement for healthy human liver with six spin-lock time (SLT) points of 1, 10, 20, 30, 40, and 50ms; the mean liver T1rho value of the healthy subjects was 42.5ms, with a range of 38.8-46.5ms. Adopting 3-SLT points of 1, 20, and 50ms for T1rho measurement could provide reliable measurement and reduce the scanning time, while 2-SLT points of 1 and 50ms do not provide reliable measurement. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Zhao, Feng. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 119-143). / Abstracts also in Chinese. / ABSTRACT --- p.i / ACKNOWLEDGEMENTS --- p.vi / LIST OF FIGURES --- p.viii / LIST OF TABLES --- p.xvi / LIST OF ABBREVIATIONS --- p.xvii / CONTENTS --- p.xxi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Conventional Magnetic Resonance Imaging --- p.1 / Chapter 1.1.1 --- Basic Principle of Conventional Magnetic Resonance Imaging --- p.1 / Chapter 1.1.2 --- T1 Relaxation --- p.2 / Chapter 1.1.3 --- T2 Relaxation --- p.3 / Chapter 1.2 --- T1rho Magnetic Resonance Imaging --- p.3 / Chapter 1.2.1 --- T1rho Relaxation --- p.3 / Chapter 1.2.2 --- Principle of T1rho Magnetic Resonance Imaging --- p.4 / Chapter 1.2.3 --- Radiofrequency Pulse for T1rho Magnetic Resonance Imaging --- p.5 / Chapter 1.2.4 --- T1rho-weighted Contrast Imaging and Application --- p.10 / Chapter 1.2.5 --- Quantitative T1rho Mapping and Application --- p.11 / Chapter 1.2.6 --- T1rho Dispersion and Application --- p.13 / Chapter 1.3 --- Thesis Overview --- p.14 / Chapter Chapter 2 --- T1rho MRI in brain aging of animal model --- p.19 / Chapter 2.1 --- Introduction --- p.19 / Chapter 2.2 --- Materials and Methods --- p.20 / Chapter 2.2.1 --- Animal Model of Brain Aging --- p.20 / Chapter 2.2.2 --- T1rho Data Acquisition --- p.21 / Chapter 2.2.3 --- T1rho Data Processing --- p.23 / Chapter 2.2.4 --- T1rho Measurement and Statistical Analysis --- p.24 / Chapter 2.3 --- Results --- p.27 / Chapter 2.4 --- Discussion --- p.38 / Chapter 2.5 --- Summary --- p.42 / Chapter Chapter 3 --- T1rho MRI in lumbar disc degeneration of human subjects --- p.43 / Chapter 3.1 --- Introduction --- p.43 / Chapter 3.2 --- Methods --- p.45 / Chapter 3.2.1 --- Subjects --- p.45 / Chapter 3.2.2 --- MR Image Acquisition --- p.46 / Chapter 3.2.2.1 --- T2-weighted MRI --- p.46 / Chapter 3.2.2.2 --- T2 Mapping Imaging --- p.47 / Chapter 3.2.2.3 --- T1rho MRI --- p.47 / Chapter 3.2.3 --- Data Processing --- p.49 / Chapter 3.2.4 --- Data Measurement and Statistical Analysis --- p.49 / Chapter 3.3 --- Results --- p.52 / Chapter 3.3.1 --- Range of T1rho/T2 Values for Discs --- p.52 / Chapter 3.3.2 --- The Relationship between NP T1rho/T2 Values and 8-level Degeneration Grading of Discs --- p.52 / Chapter 3.3.3 --- The Relationship between NP T1rho/T2 Values and 5-level Degeneration Grading of Discs --- p.55 / Chapter 3.3.4 --- The Relationship between AF T1rho/T2 Values and 8-level Degeneration Grading of Discs --- p.58 / Chapter 3.3.5 --- The Relationship between AF T1rho/T2 Values and 8-level Degeneration Grading of Discs --- p.61 / Chapter 3.4 --- Discussion --- p.64 / Chapter 3.5 --- Summary --- p.69 / Chapter Chapter 4 --- T1rho MRI in rat liver fibrosis model induced by CCl4 insult --- p.71 / Chapter 4.1 --- Introduction --- p.71 / Chapter 4.2 --- Materials and Methods --- p.73 / Chapter 4.2.1 --- Animal Preparation --- p.73 / Chapter 4.2.2 --- MR Image Acquisition --- p.74 / Chapter 4.2.2.1 --- T2-weighted MRI --- p.75 / Chapter 4.2.2.2 --- T1rho MRI --- p.75 / Chapter 4.2.3 --- Data Processing --- p.76 / Chapter 4.2.4 --- Data Measurement and Statistical Analysis --- p.78 / Chapter 4.2.5 --- Histology Analysis --- p.79 / Chapter 4.3 --- Results --- p.80 / Chapter 4.3.1 --- T1rho Measurement Reproducibility --- p.80 / Chapter 4.3.2 --- Rat Liver T1rho Values at Different Time Phase --- p.81 / Chapter 4.3.3 --- Relative Rat Liver Signal Intensity on T2WI at Different Time Phase --- p.83 / Chapter 4.3.4 --- Histology Results --- p.84 / Chapter 4.4 --- Discussion --- p.86 / Chapter 4.5 --- Summary --- p.91 / Chapter Chapter 5 --- T1rho MRI in liver of healthy human subjects --- p.93 / Chapter 5.1 --- Introduction --- p.93 / Chapter 5.2 --- Methods --- p.95 / Chapter 5.2.1 --- Subjects --- p.95 / Chapter 5.2.2 --- MR Image Acquisition --- p.96 / Chapter 5.2.2.1 --- T2-weighted MRI --- p.96 / Chapter 5.2.2.2 --- T1rho MRI --- p.97 / Chapter 5.2.3 --- T1rho Data Processing --- p.99 / Chapter 5.2.4 --- T1rho Measurement --- p.100 / Chapter 5.3 --- Results --- p.102 / Chapter 5.3.1 --- T1rho Measurement Reproducibility --- p.105 / Chapter 5.3.2 --- T1rho Value Agreement of the Fasting Status with Post Meal Status --- p.105 / Chapter 5.3.3 --- T1rho Value Agreement for T1rho Maps Constructed by Different Spin-lock Time Points --- p.106 / Chapter 5.3.4 --- T1rho Value Range of Healthy Human Subjects --- p.108 / Chapter 5.4 --- Discussion --- p.108 / Chapter 5.5 --- Summary --- p.113 / Chapter Chapter 6 --- General discussion and further work --- p.115 / References: --- p.119 / LIST OF PUBLICATIONS --- p.138

The neurophysiological basis of cognition changes with age is relatively unexplained, with most studies reporting weak relationships between cognition and measures of brain function, such as event related potentials, brain size and cerebral blood flow. Proton magnetic resonance spectroscopy (1H-MRS) is an in vivo method used to detect metabolites within the brain that are relevant to certain brain processes. Recent studies have shown that these metabolites, in particular N-acetyl aspartate (NAA), which is associated with neuronal viability, correlate with performance on neuropsychological tests or other measures of cognitive function in patients with a variety of cognitive disorders associated with ageing and in normal ageing subjects. We have studied the relationship between metabolites and cognitive function in elderly patients 3 months and 3 years after a stroke or transient ischemic attack (TIA) and in an ageing comparison group. Metabolites were no different between stroke/TIA patients and elderly controls, however, there were significant metabolite differences between stroke/TIA patients with cognitive impairment (Vascular Cognitive Impairment and Vascular Dementia) and those without. Frontal measures of NAA and NAA/Cr predicted cognitive decline over 12 months and 3 years in stroke/TIA patients and elderly controls, and these measures were superior predictors than structural MRI measures. Longitudinal stability of metabolites in ageing over 3 years was associated with stability of cognitive function. The results indicate that 1H-MRS is a useful tool in differentiating stroke/TIA patients with and without cognitive impairment, with possibly superior predictive ability than structural MRI for assessing future cognitive decline. The changes in 1H-MRS that occur with ageing and cognitive decline have implications for the neurophysiological mechanisms and processes that are occurring in the brain, as well as application to clinical diagnosis, the early detection of pathology and the examination of longitudinal change.

La neurogenèse persiste à l’âge adulte dans deux régions du système nerveux central (SNC) des mammifères : la zone sous-ventriculaire (SVZ) du cerveau antérieur et la zone sous-granulaire (SGZ) de l’hippocampe. Cette neurogenèse est possible grâce à la capacité de prolifération des cellules souches présentes dans les niches de la SVZ et la SGZ, mais en vieillissant, le cerveau subit une diminution dramatique du nombre de cellules souches neurales adultes (CSNa), une diminution de la prolifération cellulaire et une altération des niches de neurogenèse. Cependant, une importante question reste sans réponse : comment la perte tardive des CSNa est temporellement reliée aux changements de l’activité de prolifération et de la structure de la principale niche de neurogenèse (la SVZ)? Afin d’avoir un aperçu sur les événements initiaux, nous avons examiné les changements des CSNa et de leur niche dans la SVZ entre le jeune âge et l’âge moyen. La niche de la SVZ des souris d’âge moyen (12 mois) subit une réduction de l’expression des marqueurs de plusieurs sous-populations de précurseurs neuraux en comparaison avec les souris jeunes adultes (2 mois). Anatomiquement, cela est associé avec des anomalies cytologiques, incluant une atrophie générale de la SVZ, une perte de la couche de cellules sousépendymaires par endroit et l’accumulation de gouttelettes lipidiques de grande taille dans l’épendyme. Fonctionnellement, ces changements sont corrélés avec une diminution de l’activité de la SVZ et une réduction du nombre de nouveaux neurones arrivant aux bulbes olfactifs. Pour déterminer si les CSNa de la SVZ ont subi des changements visibles, nous avons évalué les paramètres clés des CSNa in vivo et in vitro. La culture cellulaire montre qu’un nombre équivalent de CSNa ayant la capacité de former des neurosphères peut être isolé du cerveau du jeune adulte et d’âge moyen. Cependant, à l’âge moyen, les précurseurs neuraux semblent moins sensibles aux facteurs de croissance durant leur différenciation in vitro. Les CSNa donnent des signes de latence in vivo puisque leur capacité d’incorporation et de rétention du BrdU diminue. Ensemble, ces données démontrent que, tôt dans le processus du vieillissement, les CSNa et leur niche dans la SVZ subissent des changements significatifs, et suggèrent que la perte de CSNa liée au vieillissement est secondaire à ces événements. / Neurogenesis persists throughout the adulthood in two regions of the mammalian central nervous system (SNC): the sub-ventricular zone (SVZ) of the forebrain and the sub-granular zone (SGZ) of the hippocampus. Neurogenesis is possible due to the proliferation capacity of stem cells present within both the SVZ and SGZ niches, but with aging, the forebrain undergoes a drastic reduction in its number of adult neural stem cells (aNSCs), a decrease of cell proliferation and an alteration of the neurogenic niches. However, a key unresolved question remains: how the onset of aNSC loss is temporally related to changes of proliferating activity and to structural alterations within the principal stem cell niche (the SVZ)? To gain insights into the initial events leading to aging-associated aNSC loss, we investigated the changes occurring to aNSCs and the SVZ niche between young adulthood and middle-age. The SVZ niche of middle-aged mice (12-months-old) was found to display reduced expression of markers for multiple neural precursor sub-populations when compared to young adult mice (2-months-old). Anatomically, this was associated with significant cytological aberrations, including an overall atrophy of the SVZ, loss of sub-ependymal cells, and accumulation of large lipid droplets within the ependyma. Functionally, these changes correlated with diminished SVZ activity and reduced number of newly born neurons reaching the principal target tissue: the olfactory bulbs. To determine whether changes were evident at the level of the SVZ stem cells, we evaluated key in vitro and in vivo parameters of aNSCs. Tissue culture experiments showed that equal numbers of neurosphere-forming aNSCs could be isolated from young adult and middle-aged forebrains. However, at middle-age, neural precursors seemed to be less sensitive to growth factors during their in vitro differentiation and displayed signs of increased quiescence in vivo. Collectively, these findings demonstrate that, with early aging, aNCS and their SVZ niche go through significant changes, and suggest that aging-associated aNSC loss is secondary to these events.

The physical complications of Type 1 diabetes mellitus (T1DM) have been understood as an accelerated ageing process (Morley, 2008). Do people with T1DM also experience accelerated cognitive and brain ageing? Using findings from research of the normal cognitive and brain ageing process and conceptualized in theories of the functional brain changes in cognitive ageing, a combination of cognitive testing and functional magnetic resonance imaging (fMRI) techniques were used to evaluate evidence of accelerated cognitive and brain ageing in middle-aged adults with T1DM. The first part of this thesis comprises a cognitive study of 94 adults (≥ 45 years of age) with long duration (≥ 10 years) of T1DM. Participants completed cognitive assessment and questionnaires on general mood and feelings about living with diabetes. Findings highlighted the importance of microvascular disease (specifically retinopathy) as an independent predictor of cognitive function. The incidence and predictors of mild cognitive impairment (MCI) were then explored. Results indicate a higher percentage of the group met criteria for MCI than expected based on incidence rates in the general population, providing initial evidence of accelerated cognitive ageing. Psychological factors were explored next. The relationship between the measures of well-being, diabetes health, and cognitive function highlighted the need for attention to patient's psychological well-being in diabetes care. Finally, a subgroup of 30 participants between the ages of 45 and 65 who differed on severity of retinopathy were selected to take part in an fMRI study. Blood oxygen level dependent (BOLD) activity was evaluated while participants were engaged in cognitive tasks and during rest. The findings provided evidence that the pattern of BOLD activation and functional connectivity for those with high severity of retinopathy are similar to patterns found in adults over the age of 65. In line with the theories of cognitive ageing, functional brain changes appear to maintain a level of cognitive function. Evidence of accelerated brain ageing in this primarily middle-aged group, emphasizes the importance of treatments and regimens to prevent or minimize microvascular complications.

La neurogenèse persiste à l’âge adulte dans deux régions du système nerveux central (SNC) des mammifères : la zone sous-ventriculaire (SVZ) du cerveau antérieur et la zone sous-granulaire (SGZ) de l’hippocampe. Cette neurogenèse est possible grâce à la capacité de prolifération des cellules souches présentes dans les niches de la SVZ et la SGZ, mais en vieillissant, le cerveau subit une diminution dramatique du nombre de cellules souches neurales adultes (CSNa), une diminution de la prolifération cellulaire et une altération des niches de neurogenèse. Cependant, une importante question reste sans réponse : comment la perte tardive des CSNa est temporellement reliée aux changements de l’activité de prolifération et de la structure de la principale niche de neurogenèse (la SVZ)? Afin d’avoir un aperçu sur les événements initiaux, nous avons examiné les changements des CSNa et de leur niche dans la SVZ entre le jeune âge et l’âge moyen. La niche de la SVZ des souris d’âge moyen (12 mois) subit une réduction de l’expression des marqueurs de plusieurs sous-populations de précurseurs neuraux en comparaison avec les souris jeunes adultes (2 mois). Anatomiquement, cela est associé avec des anomalies cytologiques, incluant une atrophie générale de la SVZ, une perte de la couche de cellules sousépendymaires par endroit et l’accumulation de gouttelettes lipidiques de grande taille dans l’épendyme. Fonctionnellement, ces changements sont corrélés avec une diminution de l’activité de la SVZ et une réduction du nombre de nouveaux neurones arrivant aux bulbes olfactifs. Pour déterminer si les CSNa de la SVZ ont subi des changements visibles, nous avons évalué les paramètres clés des CSNa in vivo et in vitro. La culture cellulaire montre qu’un nombre équivalent de CSNa ayant la capacité de former des neurosphères peut être isolé du cerveau du jeune adulte et d’âge moyen. Cependant, à l’âge moyen, les précurseurs neuraux semblent moins sensibles aux facteurs de croissance durant leur différenciation in vitro. Les CSNa donnent des signes de latence in vivo puisque leur capacité d’incorporation et de rétention du BrdU diminue. Ensemble, ces données démontrent que, tôt dans le processus du vieillissement, les CSNa et leur niche dans la SVZ subissent des changements significatifs, et suggèrent que la perte de CSNa liée au vieillissement est secondaire à ces événements. / Neurogenesis persists throughout the adulthood in two regions of the mammalian central nervous system (SNC): the sub-ventricular zone (SVZ) of the forebrain and the sub-granular zone (SGZ) of the hippocampus. Neurogenesis is possible due to the proliferation capacity of stem cells present within both the SVZ and SGZ niches, but with aging, the forebrain undergoes a drastic reduction in its number of adult neural stem cells (aNSCs), a decrease of cell proliferation and an alteration of the neurogenic niches. However, a key unresolved question remains: how the onset of aNSC loss is temporally related to changes of proliferating activity and to structural alterations within the principal stem cell niche (the SVZ)? To gain insights into the initial events leading to aging-associated aNSC loss, we investigated the changes occurring to aNSCs and the SVZ niche between young adulthood and middle-age. The SVZ niche of middle-aged mice (12-months-old) was found to display reduced expression of markers for multiple neural precursor sub-populations when compared to young adult mice (2-months-old). Anatomically, this was associated with significant cytological aberrations, including an overall atrophy of the SVZ, loss of sub-ependymal cells, and accumulation of large lipid droplets within the ependyma. Functionally, these changes correlated with diminished SVZ activity and reduced number of newly born neurons reaching the principal target tissue: the olfactory bulbs. To determine whether changes were evident at the level of the SVZ stem cells, we evaluated key in vitro and in vivo parameters of aNSCs. Tissue culture experiments showed that equal numbers of neurosphere-forming aNSCs could be isolated from young adult and middle-aged forebrains. However, at middle-age, neural precursors seemed to be less sensitive to growth factors during their in vitro differentiation and displayed signs of increased quiescence in vivo. Collectively, these findings demonstrate that, with early aging, aNCS and their SVZ niche go through significant changes, and suggest that aging-associated aNSC loss is secondary to these events.