The purpose of the proposed project is to provide the candidate with additional career development training in areas of multimodal neuroimaging and characterization of Primary Progressive Aphasia (PPA) to enable the candidate to establish a productive research program geared towards the long-term goals of: 1) delineating the pathophysiology of PPA using resting state functional MRI (rs-fMRI) and brain volumetric measurements, and 2) designing an effective treatment for aphasia. To achieve this purpose, the project includes both career development activities and a research plan designed to advance insight into the brain physiologic and structural changes in PPA. Relatively little is known about the relationship between changes in the brain language network physiology, brain tissue loss (atrophy) and clinical findings of aphasia in PPA. Based on our recent finding that PPA symptoms can exist in the absence of significant brain atrophy, the first aim of this research program is to determine whether functional connectivity in PPA is decreased in the absence of detectable atrophy. Currently, it is not known to what extent atrophy reflects the loss of neuronal versus non- neuronal tissue. Therefore the relationship between brain atrophy and changes in language network is not well understood.
Our second aim tests the hypothesis that increased atrophy results in a further decrease in network connectivity in PPA. This multimodal neuroimaging and clinical approach may enable further characterization of the language network disruption and can potentially be used to [investigate neurobiology of treatment responsiveness, gauge therapeutic interventions, and identify network targets for neuromodulatory interventions such as repetitive Transcranial Magnetic Stimulation (rTMS)]. In addition, if rs-fMRI proves to be able to identify language network change, it may prove to be a candidate biomarker to predict the path of atrophy and disease progression. Findings will also have significant impact on our understanding of aphasia and the language network in general. So far, as an investigator at the Northwestern Cognitive Neurology and Alzheimer Disease Center, I have acquired skills to analyze and interpret normal rs-fMRI data. However, to achieve the goals of this proposal and to develop autonomy, I need to advance my skills further with additional training from experts from Northwestern Clinical and Translational Imaging, and outstanding advisors outside Northwestern. With regards to volumetric measurements in PPA, I have not had the opportunity to acquire the necessary expertise. The K23 mechanism will provide protected time for me to learn volumetric measurements in PPA. The K23 mechanism will also provide the opportunity for me to collaborate with the outstanding group of experts outside Northwestern to improve my rs-fMRI and brain volumetric skills, and establish independent collaborations beyond Northwestern. [In this resubmission, in line with my long term goal, additional training components for treatment of PPA have been added. These include both speech/language, and neuromodulatory (rTMS) interventions, which eventually enable me to bridge findings from this study with language interventions]. In summary, the career development activities in this proposal aim at advancing my current knowledge and skills towards the goal of writing an R01 research grant addressing my long term goal.
This study investigates the changes in resting state functional connectivity of the language network in patients with Primary Progressive Aphasia. The pattern of language network disruption will be evaluated in patients with and without significant cortical atrophy. This multimodal neuroimaging and clinical approach will enable further characterization of the language network disruption and can potentially be used [to investigate neurobiology of treatment responsiveness, gauge therapeutic interventions, and identify network targets for neuromodulatory interventions such as repetitive Transcranial Magnetic Stimulation]. In addition, if rs-fMRI proves to be able to identify language network change, it may be used as a candidate biomarker to predict language network disruption in the absence of significant atrophy. Findings will also have significant impact on our understanding of aphasia and the language network in general.
|Gefen, Tamar; Ahmadian, Saman S; Mao, Qinwen et al. (2018) Combined Pathologies in FTLD-TDP Types A and C. J Neuropathol Exp Neurol 77:405-412|
|Bonakdarpour, Borna; Rogalski, Emily J; Wang, Allan et al. (2017) Functional Connectivity is Reduced in Early-stage Primary Progressive Aphasia When Atrophy is not Prominent. Alzheimer Dis Assoc Disord 31:101-106|