White matter pathways to cognitive aging and dementia: diffusion metrics as a correlate of aging and of age-associated cognitive functions

SummaryBackgroundIt is gratifying to note today’s long live expectancy. Unfortunately this increase in longevity is often marred by the difficulties that beset old age. Among the disabilities the greatest impact on older adults is decreasing cognitive functioning and dementia. The most common form of dementia is Alzheimer’s disease (AD). In the year 2008, over 100’000 people suffering from dementia lived in Switzerland and over 24’000 people newly contract dementia per year. AD can still not be prevented or cured. Tremendous advances in our understanding of the pathogenesis have been made in recent years, but most models are hypothetical and much more work is required to elucidate fully the myriad potential causes of dementia in order to develop reasonable treatment and preventative strategies. Abnormalities in the brain’s white matter (WM) have recently received increasing attention as potentially being central aspects of the pathogenic cascade in AD-related dementia. It is unclear at this point, however, how best to characterize WM abnormalities, whether WM abnormalities are necessary or sufficient to cause cognitive impairment related to AD, and whether WM abnormalities interact with primary markers of AD pathology. Diffusion-weighted magnetic resonance imaging (DWI) provides new insights into the microstructure of the WM. However, the tremendous potential of different DWI techniques, such as diffusion tensor imaging (DTI) or Diffusion Kurtosis Imaging (DKI), is by far not explored exhaustively. Hence, the proposed work focuses on the evaluation of different DWI metrics to investigate age related changes in the neuroanatomy of the brain. Thereby, the proposed study has two major goals: 1.To determine which DWI metrics are most strongly correlated with aging and cognition among older adults. 2.To determine which DWI metrics best predict changes in cognitive functioning.Research PlanThe overall aim of the proposed study is to determine which DWI metric is the strongest correlate of aging and of age-associated cognitive function. To reach this goal, the necessary post-processing algorithms for DTI and DKI have to be implemented and optimized, allowing stable derivations of the metrics of interest. The work will be carried out in the context of the Washington Heights Inwood Columbia Aging Program (WHICAP), which is an ongoing community-based study of cognitive aging and dementia in northern Manhattan, New York. Thorough statistical analysis will be performed to determine the sensitivity and specificity of the DWI metrics as a correlate of aging and of age-associated cognitive function. Thereby, the analysis will be performed on a whole brain voxel-by-voxel basis as well as in regions of interest based on WM tractography. The focus will be on the implementation, evaluation and optimization of the diffusion framework and thereafter on the interpretation of the statistical results.SignificanceDWI has emerged as one of the most powerful tools to understand the structural neuroanatomy of the brain and has tremendous potential for clinical applications. There are a number of metrics that can be derived from diffusion data, but there is currently no consensus in the scientific literature about which is the most sensitive and specific to answer clinically meaningful questions. A thorough evaluation of the various diffusion parameters will address this issue and will give new insight in the potential of DWI metrics to provide early biomarkers for aMCI and thus for dementia including AD. The results of this project will provide a basis for future studies and, moreover, may help to develop, guide and test new approaches for an early treating of dementia.