Faculty Bibliography

In this study, venous oxygen saturation and oxygen metabolic changes in multiple sclerosis (MS) patients were assessed using a recently developed T2-relaxation-under-spin-tagging (TRUST) magnetic resonance imaging (MRI), which measures the superior sagittal venous sinus blood oxygenation (Yv) and cerebral metabolic rate of oxygen (CMRO(2)), an index of global oxygen consumption. Thirty patients with relapsing-remitting MS and 30 age-matched healthy controls were studied using TRUST at 3 T MR. The mean expanded disability status scale (EDSS) of the patients was 2.3 (range, 0 to 5.5). We found significantly increased Yv (P<0.0001) and decreased CMRO(2) (P=0.003) in MS patients (mean+/-s.d.: 65.9%+/-5.1% and 138.8+/-35.4 mumol per 100 g per minute) as compared with healthy control subjects (60.2%+/-4.0% and 180.2+/-24.8 mumol per 100 g per minute, respectively), implying decrease of oxygen consumption in MS. There was a significant positive correlation between Yv and EDSS and between Yv and lesion load in MS patients (n=30); on the contrary, there was a significant negative correlation between CMRO(2) and EDSS and between CMRO(2) and lesion load (n=12). There was no correlation between Yv and brain atrophy measures. This study showed preliminary evidence of the potential utility of TRUST in global oxygen metabolism. Our results of significant underutilization of oxygen in MS raise important questions regarding mitochondrial respiratory dysfunction and neurodegeneration of the disease.

Background: Due to well-known markedly increased susceptibility contrast at ultra-high-field MR, this work is using 7T MR susceptibiltyweighted imaging (SWI) to better identify the histopathologic correlate of amyloid plaques containing iron and otherwise invisible subhippocampal structures of human post-mortem brain in patients with Alzheimer's disease. Methods: Post-mortem brain specimens of the frontal lobe and hippocampus were obtained from 8 patients (mean age 71.266.2 years) with clinically diagnosed AD and 6 age-matched healthy controls (72.4 66.6 years) without AD. Coronal 1w3 cm thick brain slices were preserved and fixed in 2% agar or formalin for this study. Imaging was performed on a 7.0T MR. A 24- element phased array head coil was used. High resolution 3D SWI was obtained with isotropic voxel size 150w320I=m. For imaging optimization to better visualize amyloid plaques, we varied TR, TE, bandwidth and flip angle from 30-100ms, 12-36ms, 60-140Hz/pixel and 10-40-; respectively. Results: Compared to controls, 7T SWI revealed a largely increased number of hypointense foci inADbrain samples along the cortical mantle of the frontal and entorhinal cortex due to enhanced susceptibility effects and superb signal. Figure 1 shows amyloid plaques identified with histologic slice (A) and in post-processed SWI image of the frontal cortex of an AD patient (B) as compared to a healthy control (C). The average phase value in the cortex region of AD data (2296 6 72) is significantly higher than that of control data (2032 6 64), which indicates higher iron amount in AD samples. In addition, 7T SWI also provides high resolution images for subregional hippocampal structures including CA1 CA2 CA3 subiculum, and dentate gyrus with significant atrophy of these structures in AD patients. Conclusions: Our findings suggest that SWI with optimization at ultra-high-field strength MR (i.e. 7T) has exhibited the capability to detect diminutive susceptibility contrast associated with iron deposition and otherwise invisible fine hippocampal structures with near histopathologic resolution. Therefore, SWI has great potential for direct detection and quantification of amyloid plaques in live human brain, and may become feasible in vivo in the near future

Background: White matter lesions in aging population often represent microvascular ischemic changes or demyelination and are considered as a possible early risk factor of cognitive impairment (Malgorzata et al. Alzheimer's & Dementia. 2007;3:54-57). In this study, we compare the white matter lesion volumes and RS-fMRI changes in patients with mild cognitive impairment (MCI) and control (CT) groups; and then we investigated the correlation between white matter lesion volume and functional connectivity and activity changes using resting state fMRI (RS-fMRI) in MCI patients. Methods: 17 MCI patients (age: 76.7 6 5.5 years, MMSE score: 24-28) and 14 age-matched healthy normal aging controls (age: 76.3 6 8.25 years) from ADNI database (http://adni.loni.ucla.edu) were used in this study. Based on RS-fMRI data (TR = 3sec, 3.3mm isotropic spatial resolution with 48 slices and 140 volumes), default mode network (DMN) was generated with seed placed in both areas of medial prefrontal and posterior cingulate cortices. In addition, fractional amplitude of low frequency fluctuation (fALFF) was also obtained with band-pass filtering and summarizing over 0.005-0.1Hz band and scaling to the whole band in the frequency domain to remove white and physiological noise (http://www.nitrc.org/projects/ fcon-1000). White matter hyper-intensity lesions from MRI T2-weighted FLAIR images scanned within 3 months of RS-fMRI acquisition were segmented semi-automatically (manual outlining with white matter constraints) using the FireVoxel software (Mikheev et al. J MRI. 2008;27:1235-1241) for all subjects. Results: Avariable-degree of peri-ventricular and frontal white matter lesions in both MCI patients and controls was identified.The white matter lesion load (WMLL) was significantly higher (P<0.001) in MCI patients (12.88 6 7.47 mL) compared to controls (5.1562.41 mL). RS-fMRI results showed significantly reduced (corrected P<0.05)DMNconnectivity in the medial prefrontal areas in MCI group; and reduced fALFF activity in the temporal cortex (Figure 1A). We also found significant correlations between WMLL and DMN connectivity reductions (r = 0.56, P = 0.02), and between the WMLL and fALFF reductions (r = 0.63, P = 0.01) in MCI patients (Figure 1B). Conclusions: The association between increased WMLL and decreased functional connectivity and spontaneous activity in MCI patients found in this study suggests that white matter lesions may play a role in cognitive decline in early stage of disease

BACKGROUND AND PURPOSE: Experimental studies have suggested a role for iron accumulation in the pathology of TBI. Magnetic field correlation MR imaging is sensitive to the presence of non-heme iron. The aims of this study are to 1) assess the presence, if any, and the extent of iron deposition in the deep gray matter and regional white matter of patients with mTBI by using MFC MR imaging; and 2) investigate the association of regional brain iron deposition with cognitive and behavioral performance of patients with mTBI. MATERIALS AND METHODS: We prospectively enrolled 28 patients with mTBI. Eighteen healthy subjects served as controls. The subjects were administered the Stroop color word test, the Verbal Fluency Task, and the Post-Concussion Symptoms Scale. The MR imaging protocol (on a 3T imager) consisted of conventional brain imaging and MFC sequences. After the calculation of parametric maps, MFC was measured by using a region of interest approach. MFC values across groups were compared by using analysis of covariance, and the relationship of MFC values and neuropsychological tests were evaluated by using Spearman correlations. RESULTS: Compared with controls, patients with mTBI demonstrated significant higher MFC values in the globus pallidus (P = .002) and in the thalamus (P = .036). In patients with mTBI, Stroop test scores were associated with the MFC value in frontal white matter (r = -0.38, P = .043). CONCLUSIONS: MFC values were significantly elevated in the thalamus and globus pallidus of patients with mTBI, suggesting increased accumulation of iron. This supports the hypothesis that deep gray matter is a site of injury in mTBI and suggests a possible role for iron accumulation in the pathophysiological events after mTBI

Purpose: To explore the neural correlates of the thalamus by using resting-state functional magnetic resonance (MR) imaging and to investigate whether thalamic resting-state networks (RSNs) are disrupted in patients with mild traumatic brain injury (MTBI). Materials and Methods: This HIPAA-compliant study was approved by the institutional review board, and written informed consent was obtained from 24 patients with MTBI and 17 healthy control subjects. The patients had varying degrees of symptoms, with a mean disease duration of 22 days. The resting-state functional MR imaging data were analyzed by using a standard seed-based whole-brain correlation method to characterize thalamic RSNs. Student t tests were used to perform comparisons. The association between thalamic RSNs and performance on neuropsychologic and neurobehavioral measures was also investigated in patients with MTBI by using Spearman rank correlation. Results: A normal pattern of thalamic RSNs was demonstrated in healthy subjects. This pattern was characterized as representing relatively symmetric and restrictive functional thalamocortical connectivity, suggesting an inhibitory property of the thalamic neurons during the resting state. This pattern was disrupted, with significantly increased thalamic RSNs (P </= .005) and decreased symmetry (P = .03) in patients with MTBI compared with healthy control subjects. Increased functional thalamocortical redistributive connectivity was correlated with diminished neurocognitive functions and clinical symptoms in patients with MTBI. Conclusion: These findings of abnormal thalamic RSNs lend further support to the presumed subtle thalamic injury in patients with MTBI. Resting-state functional MR imaging can be used as an additional imaging modality for detection of thalamocortical connectivity abnormalities and for better understanding of the complex persistent postconcussive syndrome. (c) RSNA, 2011

Background: Small-world network is a relatively new concept, characterized by a class of regional hubs with short communication length and high clustering coefficient. It consists of well-balanced networks with local specialization and global integration.We hypothesize that the degree and topographic pattern of cortical adaptive changes are different in mild cognitive impairment (MCI) and Alzheimer's disease (AD) and can be detected with small-world properties based on cortical thickness. Methods: 13 normal controls, 10 individuals with MCI and 10 with early AD were enrolled. The MRI scans were conducted using the 1.5T scanner. We used the 3D high resolution anatomical MPRAGE data to obtain structural small world networks based on cortical thickness measurements using Freesurfer (http:// surfer.nmr.mgh.harvard.edu/) software. The thickness of total of 156 brain structures (78 ROIs on each hemisphere of brain from Freesurfer standardized landmarks) was computed to derive the correlation matrix, which is used to generate small world graphic topology with a threshold of p < 0.0001 to maintain sparseness (Fig1). Small world properties were then computed and analyzed with in-house matlab scripts and programs from matlab-bgl (http://www.stanford.edu/~dgleich/programs/matlab-bgl/) in all subjects. Results: We found significant disruption of small-world properties in patients compared to controls. These include significantly decreased mean relative betweeness centrality (BC, a measure of path length) and highest cluster coefficient (CC) in patients with MCI and AD compared to controls. The core number was reduced in AD (29) compared to NC (23) and was increased in MCI (48). The number of edges (number of undirected connections) was also reduced in AD compared to NC (from 4842 to 3948) and was increased MCI (9584). Conclusions: Both MCI and AD showed disrupted small world properties compared to controls with higher degree in AD. However, the findings of increased core number in the superior and inferior temporal parts in patients with MCI may reflect a compensative mechanism for reduced BC and CC in the posterior cingulate and precuneus regions. Further follow-up studies of different stages of MCI are warranted. (Figure presented)

OBJECTIVE: To assess cerebral blood flow (CBF) changes in patients with mild traumatic brain injury (MTBI) using an arterial spin labelling (ASL) perfusion MRI and to investigate the severity of neuropsychological functional impairment with respect to haemodynamic changes. MATERIALS AND METHODS: Twenty-one patients with MTBI and 20 healthy controls were studied at 3T MR. The median time since the onset of brain injury in patients was 24.6 months. Both patients and controls underwent a traditional consensus battery of neurocognitive tests. ASL was performed using true fast imaging with steady state precession and a flow-sensitive alternating inversion recovery preparation. Regional CBF were measured in both deep and cortical gray matter as well as white matter at the level of basal ganglia. RESULTS: The mean regional CBF was significantly lower in patients with MTBI (45.9 +/- 9.8 ml/100 g min(-1)) as compared to normal controls (57.1 +/- 8.1 ml/100 g min(-1); p = 0.002) in both sides of thalamus. The decrease of thalamic CBF was significantly correlated with several neurocognitive measures including processing and response speed, memory/learning, verbal fluency and executive function in patients. CONCLUSIONS: Haemodynamic impairment can occur and persist in patients with MTBI, the extent of which is more severe in thalamic regions and correlate with neurocognitive dysfunction during the extended course of disease

Cerebral metabolic rate of oxygen (CMRO(2)) is an important marker for brain function and brain health. Existing techniques for quantification of CMRO(2) with positron emission tomography (PET) or MRI involve special equipment and/or exogenous agents, and may not be suitable for routine clinical studies. In the present study, a noninvasive method is developed to estimate whole-brain CMRO(2) in humans. This method applies phase-contrast MRI for quantitative blood flow measurement and T(2)-relaxation-under-spin-tagging (TRUST) MRI for venous oxygenation estimation, and uses the Fick principle of arteriovenous difference for the calculation of CMRO(2). Whole-brain averaged CMRO(2) values in young, healthy subjects were 132.1 +/- 20.0 micromol/100 g/min, in good agreement with literature reports using PET. Various acquisition strategies for phase-contrast and TRUST MRI were compared, and it was found that nongated phase-contrast and sagittal sinus (SS) TRUST MRI were able to provide the most efficient and accurate estimation of CMRO(2). In addition, blood flow and venous oxygenation were found to be positively correlated across subjects. Owing to the noninvasive nature of this method, it may be a convenient and useful approach for assessment of brain metabolism in brain disorders as well as under various physiologic conditions.