UCLA

Diseases of aging, such as Alzheimer’s, occur at the hands of many cumulative risk factors occurring over a lifetime. As with virtually all non-mendelian diseases, genetics and environment play essential and synergistic roles in disease development. Disentangling the relative contributions of risk factors will aide future prevention in youth to reduce an individual’s risk later in life. The same risk factors may also serve as biomarkers signaling brain changes in advance of disease state. Once we have successful treatments, early identification and intervention will be the best, and perhaps only way to prevent Alzheimer’s disease.

The goal of this research is to identify early cognitive and physiological changes or differences in subjects at high-risk for AD, as well as to identify pathological features that are most related to memory decline. This knowledge has strong implications for identification of both Alzheimer’s disease and the optimal targets for treatment.

In chapter 1 we use the positron emission tomography (PET) ligand [18F]FDDNP, a marker for beta-amyloid plaque and tau neurofibrillary tangle deposition, to investigate the relationship between lifestyle factors, protein deposition and severity of memory impairment. We show that BMI and age are significant predictors of plaque and tangle deposition that correlates with memory impairment and Alzheimer’s disease.

In chapter 2, we combine structural magnetic resonance imaging (MRI), cortical segmentation and the PET ligand [18F]MPPF, which selectively binds the serotonin (5-HT) 1A receptor. We quantify hippocampal 5-HT1A receptor densities in older adults because the hippocampus is integral to the formation of new memories and one of the earliest brain regions to show AD-related changes. Receptor density is a proxy for neuronal loss, and can be compared to measures of hippocampal volume obtained with cortical segmentation. We find that 5-HT1A receptor density predicts differences in memory performance across all subjects, and is highly correlated in subjects with below-average memory performance. We also see lateralization of binding density consistent with previously suggested functional differences.

In chapter 3 we investigate the relationship between anxiety and memory loss with the 5HT1A receptor, known to influence anxiety behavior, in regions previously shown to play a role in anxiety disorders such as the amygdala, insula and cingulate cortex. Though, surprisingly, we do not see a relationship between 5-HT1A receptor density and anxiety in amygdala, we do see a significant relationship between receptor density and anxiety in insula, and this relationship is also related to working memory deficits and a perceived increase in forgetfulness. Furthermore this relationship is in direct opposition in women and men. While women show a decrease in 5-HT1A receptor density with increased anxiety, men show the inverse. This supports previous suggestion of significant sex differences in the serotonin system, and a relationship between mood disorders such as anxiety and depression and risk of later cognitive decline.