Research
Research Focus
Our overarching aim is elucidating the mechanisms of age-related changes in the brain and cognition, and identifying the factors that are responsible for individual differences in trajectories of aging. Because cross-sectional design does not inform us about age-related changes and individual differences therein, we focus almost exclusively on longitudinal studies. The main themes of the current studies in the Healthy Brain Aging Laboratory are:
Differential Aging of Brain Structure
We are interested in evaluating change and variability in the rates of change in regional brain volumes, as well as regional integrity and organization of the cerebral white matter. The results of our previous studies (cross sectional comparisons and longitudinal follow-up) indicate that not all brain components age at the same rate. Association cortices, the caudate nucleus, and the cerebellum show steeper declines than the visual cortex. The hippocampus and the entorhinal cortex are likely to show nonlinear, age-accelerated course of shrinkage. We are trying to identify the antecedents of change and the modifiers of the age trajectories of structural brain declines. To do so, we collect several MRI images including MPRAGE, diffusion-tensor (DTI), susceptibility-weighted (SWI), high-resolution imaging targeting the hippocampus and its sub-regions, as well as fluid attenuated inversion recovery (FLAIR) sequence that is particularly sensitive to the abnormalities in the subcortical white matter. Examples of our longitudinal findings can be found in these articles:
https://www.ncbi.nlm.nih.gov/pubmed/15703252
https://www.ncbi.nlm.nih.gov/pubmed/26746579
https://www.ncbi.nlm.nih.gov/pubmed/21194799
Cognitive Consequences of Structural Brain Aging
Although structural changes may be separate in time from cognitive declines, some links between smaller regional volumes or faster longitudinal declines of brain regions and poorer performance on cognitive tasks have been noted. For example, we found the rate of shrinkage of the entorhinal cortex, which is usually stable until the seventh decade, is associated with reduced memory performance. Notably, the relationship between cognitive abilities and brain integrity may be bi-directional. In one longitudinal study of healthy adults, we observed such reciprocal influences among neuroanatomical and cognitive variables. Larger brain volumes at baseline predicted greater individual gains in fluid intelligence test scores, but differences in prefrontal cortex volume shrinkage were in part explained by baseline level of cognitive performance. Changes in the prefrontal white matter volume were coupled with change in cognitive performance. In examining changes in several indices of white matter organization, we found that these changes are coupled with changes in memory scores over two years. Establishing whether changes in the brain lead or trail changes in cognition requires multi-occasion studies, such as the longitudinal study that is currently underway in our lab. The examples of relevant publications on the described links between brain and cognitive change can be found at these links:
https://www.ncbi.nlm.nih.gov/pubmed/14749440
https://www.ncbi.nlm.nih.gov/pubmed/26584866
https://www.ncbi.nlm.nih.gov/pubmed/26545457
https://www.ncbi.nlm.nih.gov/pubmed/25926451
https://www.ncbi.nlm.nih.gov/pubmed/29360573
Modifiers of Brain Aging
Multiple indicators of vascular and metabolic risk, such as hypertension and elevated blood sugar become more common with age. We found that even when treated and reasonably well controlled, vascular and metabolic risk may still exert negative influence on the brain and cognition. Metabolic risk can mediate the effects of age on the white matter microstructure and iron accumulation, which in turn are associated with poorer cognitive performance. The papers describing these findings can be found here:
https://www.ncbi.nlm.nih.gov/pubmed/25771392
https://www.ncbi.nlm.nih.gov/pubmed/23767922
Multiple genes control complex cognitive functions and their brain substrates. Naturally occurring variants of specific genes affect production and expression of neurochemical compounds that modify neuroanatomy and behavior. Although these variants account for a small percentage of individual variation in brain and cognition, they are nonetheless important contributors to the emerging pattern of individual differences in human aging. For example, COMT Val158Met polymorphism was found to affect executive functions, and in our sample, Met allele homozygotes performed better than Val allele carriers on several executive functions tests as well as more complex tests of fluid abilities. Selective executive functions are also affected by the epsilon4 allele of ApoE polymorphisms known to increase the risk for Alzheimer's disease. Genetic polymorphisms associated with metabolic regulation and control of inflammatory processes are good candidates for explaining some of the age-related differences in brain and cognition. For instance, a variant in the gene that controls expression of Brain-Derived Neurotrophic Factor (BDNF) modifies memory performance in healthy adults. Notably, that variant (a met allele of the BDNF val66met polymorphism) may be more harmful to memory performance when it is combined with a modifiable metabolic risk factor such as elevated (though nominally normal) blood glucose. Recently, we observed that genetic variants related to inflammation response (IL-1β and CRP) significantly increase the burden of white-matter abnormalities beyond the known effects of age and hypertension. We observed that a polymorphism of IL-1β that is associated with higher levels of the eponymous pro-inflammatory cytokine has been linked to faster brain shrinkage and smaller hippocampal regional volumes. Select publications examining these outcomes can be found here:
https://www.ncbi.nlm.nih.gov/pubmed/28120105
https://www.ncbi.nlm.nih.gov/pubmed/21889590
https://www.ncbi.nlm.nih.gov/pubmed/22245009
https://www.ncbi.nlm.nih.gov/pubmed/25264227
Current Projects
In addition to continuing our longitudinal studies on neural and cognitive changes and their modifiers, we are currently involved in two exciting projects that use Magnetic Resonance Spectroscopy (MRS) to evaluate energetic metabolism and task-related neurotransmitter modulation. The goal is to compare younger and older adults and examine changes over time in the context of cognitive changes and modifying effects of metabolic and vascular risk on the relationships between neural and cognitive variables over time. In one project, we hope to find out how brain energy metabolism changes with age and whether these changes precede or follow declines in regional volumes and white matter microstructure. In the other project, we study age differences and changes in task-related modulation of glutamate during memory encoding. Data collection on these projects is in progress but you can learn about functional MRS from this review:
https://www.ncbi.nlm.nih.gov/pubmed/29593585
For general overview of the extant literature on the brain and cognitive aging, please see: