Cerebral Microstructure in Aging and Dementia using Advanced Quantitative MRI

如目标和目的部分所述，本研究计划的主要目标是进一步扩展我们目前的研究，研究大脑中髓鞘形成和轴突密度与认知和功能结果的关系，以及铁沉积、局部髓鞘形成和轴突密度的相互作用，使用髓鞘水分数（MWF）指标进行髓鞘量化，多壳扩散张量成像（MSDTI）进行轴突密度测绘。和敏感性成像（SWI）用于局部铁含量定量。与这些研究进一步相关的是，通过对MWF、MSDTI、SWI和CBF的联合MRI测量，在正常衰老（NA）、轻度认知障碍（MCI）和痴呆的情况下，少突胶质细胞代谢和轴突密度对局部脑血流量（CBF）的脆弱性。此外，除了认知能力下降外，痴呆症还伴有神经精神症状，包括情绪、情绪和睡眠紊乱，以及混乱、躁动和抑郁。所有这些都表明，脑干在痴呆症的发展中起着重要作用。在认知障碍和痴呆的研究中，这一区域的研究明显不足。

As indicated in the Goals and Objectives section, the main goals of this research initiative is to further expand our current research to investigate the relationship of myelination and axonal density in the brain to cognitive and functional outcomes, as well as the interplay of iron deposition, local myelination, and axonal density, using myelin water fraction (MWF) metrics for myelin quantification, multi-shell diffusion tensor imaging (MSDTI) for axonal density mapping, and susceptibility imaging (SWI) for local iron content quantification. A further important correlate to these studies is the vulnerability of oligodendrocyte metabolism and axonal density to local cerebral blood flow (CBF) through combined MRI measurements of MWF, MSDTI, SWI, and CBF, in the setting of normative aging (NA), mild cognitive impairment (MCI), and dementia. Further, in addition to cognitive decline, dementia is accompanied by neuropsychiatric symptoms including disturbances in mood, emotion and sleep, as well as confusion, agitation and depression. All of this suggests significant brainstem involvement in the development of dementia. This region is remarkably understudied in the investigation of cognitive impairment and dementia. Significant progress has been achieved during the last fiscal year. Using our advanced MRI techniques for MWF and CBF quantifications: 1- We demonstrated a quadratic, inverted U-shape, relationship between MWF and age in all brain regions investigated, suggesting that myelination continues until middle age followed by decreases at older ages. We also observed that these age-related differences vary across different brain regions, as expected. Finally, our results provide reference values for MWF values in normative aging. This work was motivated by the fact that age is the main risk factor for degenerative central nervous system (CNS) disease and associated cognitive and functional impairment. It is therefore crucial to characterize microstructural changes in the brain that occur with normal aging to distinguish them from changes caused by disease. Postmortem studies have shown that myelin degeneration is among the main sequelae of aging and may be associated with concomitant motor and cognitive decline, as well as likely being closely linked to a number of age-associated neurodegenerative disorders and dementias. Myelin, an electrical insulator essential for action potential conduction and for transporting trophic support to the neuronal axons of the CNS, is crucial for higher-order integrative functions of the brain. Our results provide evidence for nonlinear associations between age and myelin in a large sample of well-characterized adults, using a direct myelin content imaging method. 2- We investigated myelin differences with normal aging within the brainstem. In our cross-sectional investigation, we studied a large cohort of cognitively unimpaired participants spanning a wide age range and found a decrease in myelination with age in most brainstem regions studied, with several regions exhibiting a quadratic association between myelin and age. Little work has been conducted to investigate age differences in the myelin content of brainstem structures. In addition to functioning as a relay and integrative brain center, the brainstem plays an important role in motor function and pain sensation, alertness, and regulation of cardiac, respiratory, and vasomotor functions. Multiple studies suggest significant brainstem involvement in the early development of Alzheimers and Parkinsons diseases with accompanying neuropsychiatric symptoms including disturbances in mood, emotion, appetite, and sleep, as well as confusion, agitation, and depression. Therefore, characterizing age differences in brainstem microstructure could provide important insights into the functional, emotional, and motor alterations that accompany normative aging and neurodegeneration. Our study is the first investigation of MWF differences with normative aging in the adult brainstem. Our work also provides reference MWF values for the main substructures of the brainstem, providing a baseline for investigations of neurodegenerative diseases, such as Alzheimers and Parkinsons diseases. 3- We provided the first demonstration of the association between local blood supply and myelin integrity, and found that myelin content declines with CBF across a wide age range of cognitively normal subjects. Indeed, production and maintenance of myelin integrity through oligodendrocytes is critical for saltatory conduction and normal axonal function. Indeed, accumulating evidence is establishing a close relationship between myelin degeneration and several neuropathologies, including multiple sclerosis and dementia. In animal studies, it has been shown that oligodendrocytes are vulnerable to blood flow deficits, and loss of these cells may occur rapidly in response to reductions in blood flow. Indeed, myelin maintenance through oligodendrocyte metabolism is an energy- intensive process, so that myelin homeostasis is particularly sensitive to hypoxia, hypo-perfusion or ischemia. In addition to substrate delivery, adequate cerebral blood flow (CBF) is crucial for removal of metabolic by- products and neurotoxins. The oligodendrocyte cells and myelin sheets are vulnerable to various insults, including iron accumulation as well as aggregations of tau and amyloid- beta proteins. Aside from potential neuronal damage, these insults can lead to loss of oligodendrocytes or impairment of their myelin synthetic capacity; this may result in deficits in myelin production and repair during turnover, or frank demyelination. Our cross-sectional findings suggest that blood supply may significantly impact white matter integrity, specifically myelin content. We expect that this work may lay the foundation for further longitudinal investigations to establish this link and to clarify the nature of myelin damage in neurodegeneration, including Alzheimers disease. These studies may lead to new markers for disease progression as well as to therapeutic targets. 4- We provided the first demonstration of the association between cerebral iron accumuand myelin integrity, and found that iron content if higher with lower myelin content. This indicate that iron accumulation in the brain is also driven by myelin and oligodendrocytes, cells that incoporate a substential amount of iron for myelin synthesis, breakdown.