Quantitative magnetization transfer of white matter tracts correlates with diffusion tensor imaging indices in predicting the conversion from mild cognitive impairment to Alzheimer's disease

Patients with amnestic mild cognitive impairment (aMCI) have higher probability to develop Alzheimer's disease (AD) than elderly controls. The detection of subtle changes in brain structure associated with disease progression and the development of tools to identify patients at high risk for dementia in a short time is crucial. Here, we used probabilistic white matter (WM) tractography to explore microstructural alterations within the main association, limbic, and commissural pathways in aMCI patients who converted to AD after 1 year follow-up (MCIconverters) and those who remained stable (MCIstable). Both diffusion tensor imaging (DTI) and quantitative magnetization transfer (qMT) parameters have been considered for a comprehensive pathophysiological characterization of the WM damage. Overall, tract-specific parameters derived from qMT and DTI at baseline were able to differentiate aMCI patients who converted to AD from those who remained stable in time. In particular, the qMT exchange rate, RMB0, of the right uncinate fasciculus was significantly decreased in MCIconverters, whereas fractional anisotropy was significantly decreased in the bilateral superior cingulum in MCIconverters compared to MCIstable. These results confirm the involvement of WM and particularly of association fibers in the progression of AD, highlighting disconnection as a potential mechanism

Molecular, dynamic, and structural origin of inhomogeneous magnetization transfer in lipid membranes

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136337/1/mrm26210.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136337/2/mrm26210_am.pd

Epileptic encephalopathy associated human GABRB mutations disrupt GABAA receptor function and results in Lennox-Gastaut syndrome in Gabrb3+/D120N knock-in mice.

Epileptic encephalopathies (EEs) are catastrophic childhood epilepsies with intractable seizures, developmental delays, and cognitive impairment. I determined the functional impact of five de novo GABAA receptor β subunit gene (GABRB) mutations identified in triads with a proband with one of two EEs⎯Infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). In HEK293T cells, the major effects of the LGS-associated GABRB3(D120N, E180G, Y302C) mutations were reduced GABA-evoked currents due to reduced channel open probability and burst duration. While IS-associated GABRB3(N110D) and GABRB1(F246S) mutations altered current rise time and deactivation due to reduced channel open probability and burst duration for the GABRB3(N110D) mutation, and reduced channel conductance and opening frequency for the GABRB1(F246S) mutation. These alterations in GABAA receptor channel function should reduce neuronal inhibition, leading to seizures. Thus, these data provide strong evidence for a contribution of GABRB mutations to LGS and IS pathology. To understand the role of these mutations in vivo, we generated a knock-in mouse with the Gabrb3(D120N) mutation (Gabrb3+/D120N). I found that Gabrb3+/D120N mice had early onset epileptic spasms from P14-P17 and multiple types of seizures in adulthood including typical and atypical absence, myoclonic, tonic, and generalized tonic-clonic seizures. The predominant seizure type in adult Gabrb3+/D120N mice were absence seizures (~400/day), which are the characteristic seizures of LGS. The gabrb3+/D120N mouse is the first mouse model of LGS and the first mouse model with spontaneous atypical absence seizures and LGS behavioral comorbidities. Gabrb3+/D120N mice will aid in understanding the pathophysiology and treatment of LGS

Myelin sensitivity in quantitative magnetization transfer and diffusion tensor imaging in an animal model of multiple sclerosis

Conventional MRI is sensitive to detect brain abnormalities non-invasively through excellent contrast generated by variation in relaxation times and water proton density. However, conventional MRI lacks the specificity and quantitation to specific pathologies and tissue components such as myelin. Myelin is the major constituent of white matter ─an insulating macromolecular sleeve wrapped around axons of brain cells. Loss of white matter, specifically myelin leads to severe motor and cognitive deficits in diseases such as multiple sclerosis. Advanced quantitative MRI methods such as quantitative magnetization transfer (qMT) and diffusion tensor imaging (DTI) have emerged as putative biomarkers that improve sensitivity, specificity and provide quantitative metrics to measure myelin. qMT and DTI are model based quantitative techniques, which provide sub-voxel information of the underlying tissue architecture. qMT is sensitive to the tissue macromolecular content, whereas DTI is sensitive to tissue microstructure. Pool size ratio (PSR, a qMT parameter) and radial diffusivity (RD, a DTI parameter) provide an indirect quantitative measure of myelin. However, their relative sensitivities and specificities to myelin are unclear. qMT and DTI are based on different physical principles and may provide complementary information. While histology is the gold standard for myelin quantification, it can only be performed postmortem or through invasive biopsies. Thus, systematic quantitative MRI and histological validation studies are essential to determine the specific sensitivities of non-invasive quantitative metrics. Although, limited data is available on such studies due to their tedious, time intensive and complex nature. My thesis work addresses this gap by performing quantitative MRI and histological validation on a relatively new animal model of multiple sclerosis (MS), which recapitulates the inflammatory and non-inflammatory demyelinating phases seen in patients. The animal model was characterized using structural MRI, qMRI and histological methods. To enable quantitative comparisons amongst MRI and histological parameters, detailed processing protocol were designed and implemented including 3D qMT and DTI protocols and histological pipeline. In vivo and ex vivo studies were performed and qMT and DTI metrics were correlated with histology and among each other to determine their specific sensitivities. Furthermore, in an attempt to translate the animal work to clinical settings, a fast qMT sequence with GRASE readout was tested on human scanners. In conclusion, we found that PSR, and RD are sensitive to histological myelin content with PSR having the strongest correlation