Highly-sensitive imaging markers for early detection of Alzheimer's Disease using multi-view connectomics 

(PI: Alex Leow)

1R21AG056782-01

Alzheimer's disease (AD) is the most common form of dementia, with the number of affected Americans expected to reach 13.4 million by the year 2050. While it is well known that AD leads to progressive neuronal death, the exact mechanism of AD remains elusive. Currently, a definitive diagnosis can only be reached by autopsy or brain biopsy, and the neurodegenerative processes in two AD patients can follow very different courses. Further, treatment options for AD remain limited, let alone cure. For this reason, non-invasive neuroimaging has been extensively investigated in the hope that it may provide more sensitive markers for screening and early detection of AD. Yet, despite the amount of resources devoted to AD imaging research, CSF Tau and A?42 continue to outperform any non-invasive imaging markers. Multimodal connectomics, including functional and structural connectome (derived from fMRI and diffusion MRI respectively), has the potential to gain system-level structure- function insights into the mechanisms of AD and thus offers a novel platform for developing new diagnostic strategies. Despite a number of interesting connectome findings in recent years, few of these connectome results have been replicated independently or proven clinically relevant, which can be partially explained by the sensitivity to parameter settings during preprocessing and connectome construction, such as the choice of brain parcellation and the type of fMRI time series correlations (full versus partial) or tractography (deterministic or probabilistic). Moreover, conventional connectome approaches usually focus on scalar summary statistics (e.g., nodal or edge-wise measures) using linear statistical techniques, which fit at each node (or edge) independent of other nodes (or edges) and thus discard important informative graph structure. Instead, this proposal will develop a multi-view connectome framework that homogenizes multiple instances of stable and reproducible high-level connectome properties across modalities and across spatiotemporal scales. This framework will be applied and cross-validated using two independent AD cohorts (Alzheimer's Disease Neuroimaging Initiative or ADNI and Wisconsin Alzheimer?s Disease Research Center cohort or Wisconsin ADRC). The identified connectome features can serve as the potential non-invasive markers for guiding the AD diagnosis.


Improving white matter integrity with thyroid hormone 

(PI: Olusola Ajilore)

5R21NS095723-02

The ability to promote and support remyelination has wide-ranging implications for a number of neuropsychiatric conditions from multiple sclerosis to major depression. Pre-clinical evidence has demonstrated that thyroid hormone treatment, in the form of triiodothyronine (T3) or tetraiodothyronine (T4), can promote and support remyelination by increasing myelin basic protein mRNA and protein, oligodendrocyte proliferation and maturation, and fractional anisotropy (a diffusion imaging measure of white matter integrity). Pilot data from our own studies suggest that baseline thyroid status is correlated with the integrity of white matter tracts associated with major depression. To date, the impact of thyroid hormone administration on white matter tracts has not been studied in vivo in adult humans. The purpose of the proposed pilot study is to examine changes in white matter tract integrity using high angular diffusion imaging and multi-component relaxometry in a population of subjects clinically indicated to receive thyroid hormone for hypothyroidism. We will scan patients with hypothyroidism at the initiation of treatment and at three and six months after starting thyroid hormone treatment. We will also administer scales assessing mood and cognition which have been shown to correlate with white matter integrity. We hypothesize that thyroid hormone treatment will be associated with an increase in fractional anisotropy, a decrease in radial diffusivity, and an increase in the myelin water fraction (markers of improved myelination) that will correlate with improvements in cognition and mood ratings. If successful, this will be the first demonstration of improved white matter integrity with thyroid hormone replacement and pave the way for therapies designed to restore structural brain connectivity