UCLA

Alzheimer's dementia is a rising public health crisis that will have an unprecedented social and economic impact in the near future, as elderly individuals make up the fastest growing segment of the population worldwide. The greatest single risk factor for Alzheimer's disease is age, though many genetic and environmental factors also influence disease onset and progression. While current treatment options are sparse and no cure exists, it is critical to (1) identify the disease at its earliest stages, before irreversible brain degeneration has occurred and (2) to develop alternative strategies for reducing dementia risk based on aspects of health that are currently modifiable, such as cardiovascular health as one example. If we can identify individuals who are at high risk for developing Alzheimer's dementia, but who have not yet experienced major neurodegeneration, then it may be possible to apply these alternative strategies to preserve brain health into old age.

In regards to the first aim, brain MRI scans identify robust signatures of Alzheimer's dementia at early stages. In my work, we have expanded upon existing brain-based MRI biomarkers by demonstrating changes in caudate nucleus shape in Alzheimer's disease and by showing that patterns of thinner cortical gray matter are associated with longitudinal expansion of the lateral ventricles. The caudate nucleus is a subcortical gray matter structure typically associated with motor planning, but is also involved in procedural memory, and is affected by the molecular pathology of Alzheimer's disease. The lateral ventricles are a fluid-filled space located at the center of the brain, which expand as brain tissue is lost in aging and dementia, within the fixed volume of the skull. Both of these biomarkers can be automatically measured from brain scans with high reliability and often with less manual intervention compared to other brain structures (such as the hippocampus). These biomarkers makes are candidates for use in clinical trials or, in the case of the lateral ventricles, even in an individual to assist in dementia diagnosis. My studies provide further validation for the use of these biomarkers with additional information on the clinical implications of structural changes in these structures.

For the second aim, I investigated blood levels of two potentially modifiable compounds (thyroid hormones and homocysteine) that have been linked to dementia risk and cognition in the elderly. Alterations in thyroid hormone levels and elevated homocysteine levels have separately been associated with increased dementia risk and cognitive decline in the elderly. My results demonstrate that homocysteine and thyroid hormones levels measured are significantly associated with structural brain differences in the elderly. I found that elderly individuals with elevated homocysteine levels were more likely to have reduced cortical gray matter in bilateral frontal, right temporal, bilateral sensory, motor, and visual areas. In another study, we found that higher levels of thyroid hormone (free thyroxine, fT4) within the normal range were associated with both brain tissue expansion and contraction relative to lower levels. These two compounds are modifiable because interventions exist to modify the levels of these compounds and it's possible to measure their levels using a blood test. While these interventions are not without risk and involve special consideration in the elderly, it is important to understand the relationship between these modifiable health factors and brain structure in the elderly. As more evidence accumulates, if the connection between these health factors, dementia risk and brain deterioration is strong enough, we may discover new avenues for preserving brain health into old age.