Date of Award

4-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

David Eidelberg, MD

Abstract

Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are frequently misdiagnosed, leading to ineffective patient management as well as sample contamination in clinical drug trials. Biomarkers that improve the accuracy of early diagnosis of dementia syndromes are essential for resolving theses issues.

We hypothesized that bvFTD has a specific covariance pattern of metabolic disruption. Our hypothesis was that this bvFTD related pattern (bvFTDRP) is unrelated to Alzheimer’s disease related pattern and the default mode network. In our hypothesis, we expected that bvFTDRP would not significantly express in patients with AD, thus can be used as a biomarker to differentiate AD from bvFTD at single case level.

To this end, FDG PET data from 10 clinically confirmed bvFTD patients and 10 age and gender matched healthy controls underwent spatial covariance mapping with principal component analysis to identify an abnormal network topography associated with bvFTD (generic bvFTD-related metabolic pattern, bvFTDRP). Subject scores for the first principal component (PC1, VAF=21.12%) significantly discriminated bvFTD patients from healthy controls (validation p< 0.0001). This bvFTDRP was characterized by covarying metabolic reductions in the anterior cingulate cortex, medial frontal lobe, inferior frontal gyrus, orbitofrontal cortex and insula. This topography demonstrated a close voxel-wise correlation (r=0.71; p< 0.001) with an analogous disease-related pattern identified by analysis of FDG PET data from a combined group comprised of 7 bvFTD subjects with confirmed FTLD pathology and 7 healthy subjects scanned at Technische Universität München. Interestingly, the bvFTDRP exhibited a significant voxel-wise correlation (r=-0.64, p< 0.001; Figure 2B) with the previously characterized normal default mode network (DMN) topography. Nonetheless, the bvFTDRP topography was unrelated (r=-0.02; Figure 2C) to the recently characterized Alzheimer’s disease-related covariance pattern (ADRP) topography. Indeed, bvFTDRP expression levels differed for bvFTD and AD patients (p< 0.001).

In conclusion, bvFTDRP was characterized by disease-related topographical features, involving key regions in the normal DMN. bvFTDRP expression levels (subject scores) discriminated between bvFTD subjects and healthy controls as well as AD patients.

Download

Share

COinS