Perceived social discrimination, a salient chronic psychosocial stressor, has an adverse effect on physical and mental health. Cumulative stress compromises adaptive physiologic processes and triggers changes in hypothalamic-pituitary-adrenocortical (HPA) axis functioning. The hippocampus is critical for episodic memory and mediates the HPA stress response. Animal models have demonstrated increased vulnerability of the hippocampus to stress-induced morphological alterations and dysfunction. Previous research has shown that greater psychosocial stress is related to poorer episodic memory performance in older adults. Diffusion-weighted imaging (DWI) studies strongly support the role of the uncinate fasciculus (UF) in episodic memory. Furthermore, psychosocial stress has been associated with white matter (WM) microstructural abnormalities in the UF. Although the effect of chronic psychosocial stress is well established, the effects of social discrimination on WM integrity and episodic memory are not well understood. In this study, we tested the hypothesis that greater perceived social discrimination in older adults is associated with poorer episodic memory performance and structural abnormalities of the UF tract. Twenty-eight participants (63.8 – 73 years, 57.1% female, 42.9% African American) reported experiences of discrimination (EoD) and perceived stress (PSS) and were assessed for episodic memory. High angular resolution diffusion imaging (HARDI) scans were analyzed with probabilistic tractography to examine associations of UF diffusion metrics with EoD scores and episodic memory performance. Spearman’s rank correlation determined a significant positive association between EoD and PSS scores (rs(28) = 0.45, p = 0.017), suggesting perceived discrimination is a chronic stressor and may be a social determinant of health. However, contrary to our expectations, neither EoD nor PSS were significantly related to episodic memory performance and UF diffusion metrics. Future longitudinal research to examine associations between perceived discrimination, episodic memory and WM microstructure in a large cohort is warranted.

Adolescence is a period of time when the brain undergoes profound development. Myelination is a maturational process in which oligodendroglia project out lipid-rich ramifications which wrap and insulate axons. This is crucial for effective neurotransmission between brain regions and, if compromised by pharmacological insults such as alcohol, can have long-term implications on behavior and cognition. We have previously shown that adolescent alcohol impacts males and females differentially, however it remains unknown how alcohol impacts oligodendroglia during development. The goal of this study was to determine the cellular dynamics of the oligodendroglia in male and female mice through development with and without alcohol exposure. Our results suggest that sexually dimorphic temporal dynamics exist within oligodendroglia. Specifically, this population of cells is notably dynamic during adolescence in males while stable in females. In addition, preliminary studies show that alcohol may cause a restriction on differentiation of oligodendroglia in male but not female mice. Further understanding of sex differences in the mechanisms of alcohol-induced change to oligodendroglia development could create the foundation for targeted, specific therapeutic agents and allow for individualized treatment of patients suffering from alcohol use disorders and potentially other addictions.

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The diagnostic lesions of neurodegenerative tauopathies, such as chronic traumatic encephalopathy (CTE) and Alzheimer’s disease (AD), are located in the cortex, however, white matter pathology is a contributing factor to neurodegeneration. At all stages of disease, white matter axonal and glial morphological abnormalities are present in CTE. Similarly, white matter changes may emerge before cortical pathology in AD. White matter irregularities bear functional consequences, as they are associated to some of the most common and onerous symptoms of these diseases, like cognitive deficits and depression. Individuals with AD present with both reduced white matter integrity and cognitive symptoms starting early in disease progression. In CTE, which is triggered by repetitive head impacts (RHI), individuals are particularly vulnerable to white matter damage as RHI exposure alone is sufficient to injure white matter tracts and induce depression symptoms. In this dissertation, I investigated the cellular and molecular presentation of white matter glial cells, including astrocytes, oligodendrocytes (OLs), and microglia in CTE and AD as compared to controls. To investigate white matter pathology, I examined glial cells on a cellular level. Neuropathologically-verified CTE samples were compared to RHI-experienced controls, with both groups containing samples with and without depressed mood. CTE with depressed mood had reduced myelin and increased neuroinflammatory peripheral cells compared to non-depressed CTE and contained increased numbers of microglia compared to non-depressed CTE and control samples. Using single-nucleus transcriptomics in neuropathologically-verified CTE samples compared to matched RHI-naïve controls, OL loss, iron aggregates, OL iron trafficking dysregulation, and two distinct astrocyte subpopulations were detected in CTE white matter. AD white matter, compared to the same control samples in the same brain region, was also depleted of OLs by single-nucleus transcriptomics. However, OLs did not demonstrate iron-related transcriptional profile like those in CTE and, in further contrast, displayed increased numbers of microglia and astrocytes. Together, these findings implicate previously uncharacterized white matter glia in the neurodegenerative process of CTE and AD and further elucidate the etiology of neurodegeneration-related symptoms in CTE. These findings may aid in the development of therapeutics targeting glial contributions to the pathologic processes of both CTE and AD.

No description available.

No description available.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23776号 / 医博第4822号 / 新制||医||1057(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 花川 隆, 教授 古川 壽亮, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

It has been known for almost two decades that the water proton NMR signal of diffusing water molecules in brain white matter undergoes a non-monoexponential decay with increasing diffusion gradient factor b. With the help of numerical simulations and analytical expressions, much effort has been directed to describing the signal decay and to extracting relevant biophysical features of the system under investigation. However, the physical basis of such nonmonoexponential behavior is still not properly understood. The primary difficulty in characterizing this phenomenon is the variation in behavior in the different directions of diffusion measurement. A combined framework that accounts for the diffusion process in all directions requires several parameters. Addition of many such parameters renders a model to be unwieldy and over-complicated, but over-simplifications can be shown to miss crucially relevant information in the data. In this thesis, I have attempted to handle this problem with simple measurements that span a wide range of parameter space. Compared to often-performed measurements that probe diffusion over a time-scale of 50-100 ms with relatively low diffusion weighting, the measurements here have been done for very short diffusion times of 2 ms and also very long diffusion times up to 2 s. The temperature dependence of the diffusion coefficients has also been extensively probed. To avoid problems related to gross tissue heterogeneity, diffusion-weighted MR imaging in vivo was performed with ultra-high resolution. These simple measurements allowed sequential assessment of many possible arguments that could have led to such non-monoexponential decay curves. Finally, it was concluded that the water in the glial processes was the major contributor to the non-exponential decay, giving rise to a \''slow\'' component both along the axonal fibers and transverse to them.

White matter changes (WMC) seen on CT and MRI brain scans of healthy subjects and of vascular or dementia patients are strongly associated with age. Their pathogenesis is still under debate, and associations with vascular risk factors have varied according to studies. Their prognostic meaning, both in the general population and in stroke patients, is also not completely established. I systematically reviewed the literature on prevalence and associations of WMC and then evaluated CT and MRI scans of the first 8 years of a population-based study of all strokes and TIA in Oxfordshire (OXVASC). In this population I researched sex and age-specific associations between WMC and different types of strokes (TOAST), different components of blood pressure, and possible vascular risk factors. I also looked into their prognostic meaning for stroke recurrence and outcome, cognitive performance and mortality. 1840 patients were assessed by MRI (520) and/or CT (1717). White matter changes were independently associated with the lacunar type of stroke. The association with hypertension was confirmed (using 10 years of pre-morbid blood pressure readings), and it was particularly strong in the younger patients, mainly for diastolic hypertension. There was no association with blood pressure variability and peripheral pulse pressure. Hypercholesterolaemia, diabetes, smoking, ischaemic heart disease, carotid stenosis and atrial fibrillation were not associated with white matter changes. There was also no association with gender. Severe WMC posed a higher risk of disability and cognitive impairment at one year from the stroke, and of death in the following 10 years. This is the first study on white matter changes associations and on their prognostic meaning, to be set in a large population-based cohort of stroke and TIA. I confirmed the association between white matter changes and higher blood pressure, in particular diastolic hypertension. I also showed the association with lacunar type of stroke to be independent from vascular risk factors, and WMC to reduce life expectancy and functional and cognitive outcome of patients with stroke.

White matter hyperintensities (WMH) are commonly found as bright regions in brain MRI images in older individuals. They are associated with various neurological and vascular diseases, such as stroke, dementia, and cardiovascular disorders. WMH is also one of the seven radiological parameters included in the idiopathic normal pressure hydrocephalus (iNPH) Radscale, used to grade the radiological signs of normal pressure hydrocephalus. The radiological patterns are highly heterogenous, making quantification and classification of WMHs complex. In this project, an automated method for quantitative and qualitative assessment of white matter hyperintensities was developed based on the deep learning architecture nnU-Net.  Different configurations of the nnU-Net network were trained on a publicly available dataset from the 2017 Medical Image Computing and Computer Assisted Invention Society (MICCAI) WMH segmentation challenge constituting different grades of WMHs, and eventually ensembled to produce the final output of the segmentation model. Based on the segmentation result, a volumetric assessment was performed using Fazekas scale, which can then be used as one of the essential radiological parameters in the iNPH Radscale. Furthermore, the pipeline subdivides and classifies the hyperintense regions based on spatial information and T1-signal intensity, which is believed to have a significant impact on the pathology of the WMHs.  The final pipeline accurately segments WMHs from T1-weighted and FLAIR MRI images with a Dice’s similarity coefficient of 0.81, quantitatively classifies each case according to Fazekas scale and further subdivides each hyperintense voxel based on its location in the brain and intensity in the T1-weighted image. Hopefully, this can serve as a meaningful tool in the diagnosis of iNPH as well as future research aiming to fully understand the clinical implications of different types of WMHs.