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.

Project Narrative The goal of this proposal is to investigate the structural and network changes in the human cerebellum over two years in middle aged and older adults, with respect to both motor and cognitive performance declines, and with respect to sex differences in older males and females. The cerebellum is involved in motor learning, postural control, and a variety of cognitive behaviors, and cross-sectional evidence suggests that it may be one of the earliest areas to show age-related shrinkage in volume. Relevant to public health, the inclusion of the cerebellum in our models of aging stands to better predict performance declines and explain these patterns in both males and females, and will also provide an important new target for research with related to age-related diseases such as Alzheimer’s, and with respect to interventions that may improve quality of life and health for older adults.