A longitudinal investigation of the cerebellum in adulthood: anatomical and network changes, motor function, and cognition

项目摘要 美国人口的迅速老龄化给我们的社会和医疗保健系统带来了新的挑战。了解导致运动和认知能力下降的因素对于帮助老年人保持生活质量和独立性至关重要。此外，有必要更好地了解与年龄相关的标准化变化的模式，以便查明可能指示病理学的不同轨迹，特别是与阿尔茨海默病相关的轨迹。了解性别差异也非常重要，因为老年女性受到阿尔茨海默病的影响更大，摔倒的次数更多，而且比老年男性更虚弱。虽然对大脑皮层的研究扩大了我们对衰老的理解，但小脑的作用却被忽视了。小脑占总脑体积的10%，包括大脑中一半以上的神经元，是通过非侵入性脑刺激进行干预的特别好的靶点。此外，它对运动和认知功能都有贡献，并在老年人中显示出体积的性别差异，这可能部分是由于更年期荷尔蒙的变化以及雌激素对小脑的作用。在研究老化小脑的有限工作中，它的体积下降仅次于海马体，动物模型表明，小脑衰老开始得比海马体早。因此，将小脑包括在大脑和行为变化的模型中，代表了一种创新的方式，可以改善对与年龄相关的表现下降的理解，而且实际上可能比单独使用大脑皮层做得更好。初步研究结果表明，小脑衰退可能开始于中年，而且在对衰老的横断面研究中，小脑结构与运动和认知表现有关。在这里，一个研究小脑、衰老和性别差异的专家团队将招募150名年龄在35岁以上的健康成年人(75名男性，75名女性)，进行为期两年的小脑和中老年行为的纵向研究。这项建议的目的是量化局部小脑体积、小脑-丘脑-皮质网络以及运动和认知功能，以研究小脑和行为轨迹。目标1将量化小脑结构和网络随时间的变化，以确定这些轨迹在成年期和衰老过程中的变化。AIM 2旨在研究大脑-行为关系，并确定小脑变化与运动和认知能力下降的关系。目标3将探索小脑和行为轨迹的性别差异，重点是更年期激素变化的影响。所有这三个目标都将包括探索性分析，调查小脑、前额叶皮质和海马体的相对贡献。预期的结果将对我们对大脑和大脑老化的理解产生重大影响，并改进我们成年后大脑和行为变化的模型。研究小脑轨迹将扩大我们对健康老龄化的了解，并有望为包括阿尔茨海默氏症在内的与年龄相关的疾病提供新的研究目标。

Project Summary The rapid aging of the population of the United States presents new challenges to our society and healthcare system. Understanding the factors that contribute to declines in both motor and cognitive performance is crucial for helping older individuals maintain their quality of life and independence. Further, a better understanding of the patterns of normative age-related change is necessary in order to pinpoint diverging trajectories that may be indicative of pathology, particularly as related to Alzheimer’s disease. Understanding sex differences is also of great importance as older women are disproportionately impacted by Alzheimer’s disease, suffer from more falls, and are more frail than older men. While research investigating the cerebral cortex has expanded our understanding of aging, cerebellar contributions have been overlooked. The cerebellum makes up 10% of the total brain volume, includes more than half of all the neurons in the brain, and is an especially good target for intervention via non-invasive brain stimulation. Further, it contributes to both motor and cognitive function, and shows sex differences in volume in older adults, that may be due in part to hormonal changes with menopause and the action of estrogen on the cerebellum. In the limited work investigating the aging cerebellum, its volumetric declines are second only to those of the hippocampus, and animal models suggest that cerebellar senescence begins sooner than in the hippocampus. Thus, including the cerebellum in models of brain and behavioral change represents an innovative way to improve understanding of age-related performance declines, and may in fact do a better job than the cortex alone. Preliminary findings indicate that cerebellar declines may begin during middle age, and that the structure is associated with motor and cognitive performance in cross-sectional investigations of aging. Here, an expert team of cerebellar, aging, and sex difference researchers will recruit a group of 150 healthy adults over the age of 35 (75 males, 75 females) for a 2-year longitudinal study of the cerebellum and behavior in middle age and older adulthood. The objective of this proposal is to quantify regional cerebellar volume, cerebello-thalamo-cortical networks, and motor and cognitive function to investigate cerebellar and behavioral trajectories. Aim 1 will quantify changes over time in cerebellar structure and networks to define these trajectories across adulthood and in aging. Aim 2 is designed to investigate brain-behavior relationships and determine how cerebellar changes relate to motor and cognitive performance declines. Aim 3 will explore sex differences in cerebellar and behavioral trajectories, with a focus on the influence of menopausal hormonal changes. All three aims will include exploratory analyses that will investigate the relative contributions of the cerebellum, the prefrontal cortex, and the hippocampus. The expected results stand to have a significant impact on our understanding of the aging mind and brain and improve our models of brain and behavioral change in adulthood. Investigating cerebellar trajectories will expand our knowledge of healthy aging, and stands to provide new targets of investigation with respect to age-related diseases, including Alzheimer’s.