טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentIrit Dolgopyat
SubjectBrain Networks Dynamics Following Neurodegeneration
DepartmentDepartment of Medicine
Supervisor Professor Kahn Itamar
Full Thesis textFull thesis text - English Version


Abstract

A central challenge in dissecting the nature of changes occurring in brain pathologies, ranging from neurodegenerative processes to normal atrophy occurring with aging, is diagnosing the most prominent functional alterations. Identifying functional changes is critical since they usually precede irreversible events, such as cell death. Although studied extensively, the time course and nature of structure-function changes occurring due to neurodegenerative processes, remain fundamentally underspecified. Here we sought to develop a platform that will allow characterizing brain-wide structural and functional changes that occur following pathological neurodegeneration and moderate atrophy caused by aging. We examined changes in anatomical measures and coherent spontaneous fluctuations in the functional magnetic resonance imaging (MRI) signal (termed intrinsic functional connectivity MRI [fcMRI]), a signal demonstrated to reflect functional connectivity. Acclimatization of awake mice in a head-posted position during fMRI enabled longitudinal imaging. The CK-p25 Alzheimer's disease-like inducible mouse model was used to study the effect of progressive neurodegeneration mediated by overexpression of the cell-cycle protein p25 in the forebrain. Anatomical changes were observed as early as three weeks after disease onset, followed by robust degeneration. Quantitative anatomical analyses twelve weeks following disease onset revealed dramatic cortical shrinkage, of up to 55%, and hippocampal shrinkage, of up to 40%. In contrast, the total cerebrospinal fluid volume in CK-p25 increased up to 476%. Despite the extensive neurodegeneration, fcMRI was only selectively affected, with the hippocampal memory system showing decreased functional connectivity to sensory and association cortices. Additionally, hippocampal subfields, striatum, and somatosensory cortex, demonstrated that bilateral functional connectivity (also termed homotopic connectivity), a hallmark of fcMRI in intact animals and humans, was disrupted, while in auditory and orbitofrontal cortices, it remained unchanged. Functional connectivity analyses revealed altered connectivity in association cortices at eight weeks following disease onset, while sensory cortices remained unchanged, suggesting that association cortices, as seen in humans, are more sensitive to the disease process. We next sought to test the impact of aging-related structural and functional changes. Thirteen-month-old wild-type mice demonstrated a decrease of 13% in cortical volume, without change in hippocampal volume. Aged animals showed increased functional connectivity of association and sensory cortices to parahippocampal regions and decreased functional connectivity of association areas to the hippocampus. Similar to CK-p25, aged animals demonstrated disrupted hippocampal and striatal homotopic connectivity and preserved functional connectivity in auditory cortex. Unlike CK-p25, aged mice demonstrated conserved functional connectivity in somatosensory cortex, but disrupted orbitofrontal homotopic connectivity. Analysis quantifying overall functional changes revealed that unlike the CK-p25, aged animals demonstrated a significant decrease in structure-function correlation in sensory but not association cortices and an overall decrease in structure-function measures. Collectively, we established a platform and a general approach to acquire and analyze longitudinal imaging of mouse models. Specifically, we studied the structure-function relations in a rapid progressive neurodegenerative condition and in aging. We linked the structural changes to potential functional consequences and proposed a novel analytic approach to study these changes. Taken together, this work has the potential to facilitate finding functional markers that discriminate between normal aging and pathological neurodegeneration.