Faculty Bibliography

Purpose: Normal neuronal activity is tightly linked to and depends on the increase of blood flow for instantaneous supply of oxygen and glucose. This study is to evaluate whether there are cerebral blood flow (CBF) regulation abnormalities in MS with measurement of cerebrovascular reactivity (CVR) using hypercapnia perfusion MRI. Materials and Methods: Sixteen patients with MS (14 relapsing remitting and 2 secondary progressive) (mean age: 45.1+14.2 years, mean EDSS: 2.9+1.6) and age-matched 13 healthy controls (mean age: 44.5+12.2 years) were recruited for this study. CO2 is a potent vasodilator, and an increase of CO2 tension in blood (referred to as hypercapnia) is known to cause CBF increase. Such CBF changes were measured with a standard pseudo-continuous arterial spin labeling (pCASL) MRI at 3T, with quantitative CBF (ml/min/100g) maps generated during both room air and hypercapnia (mixed 5%CO2, 21%O2, and 74%N2) exposure. The imaging parameters of pCASL include TR/TE=3950/17ms, 52 repetitions, FOV=22cm, in-plane matrix=64x64, slice thickness=5mm, labeling duration=1500ms, postlabeling delay=1230ms, and label location = 84mm below AC-PC line. End-tidal CO2 (EtCO2) was recorded continuously during the scan with a capnograph device and was used as an input function in the analysis. The CVR was calculated as (% change in CBF comparing CO2 inhalation to room-air breathing) divided by (EtCO2 during CO2 inhalation - EtCO2 during room-air breathing). Segmented whole brain grey matter (GM), white matter (WM), and brain parenchymal CVR were calculated for the group analysis. Results: The averaged CVR (%CBF/mmHg EtCO2) showed significant difference for whole brain parenchymal (P=0.009), GM (P=0.008), and WM (P=0.03) between patients (4.74+0.88%, 4.89+1.08%, and 4.73+1.02%) and healthy controls (3.46+1.51%, 3.51+1.47%, and 3.53+1.83%, respectively). There was a significant correlation between brain parenchymal CVR and EDSS (r=-0.69, P=0.007). Whole brain CVR changes correlate with fractional brain p!

Purpose: To investigate the integrity of the default-mode network (DMN) by using independent component analysis (ICA) methods in patients shortly after mild traumatic brain injury (MTBI) and healthy control subjects, and to correlate DMN connectivity changes with neurocognitive tests and clinical symptoms. Materials and Methods: This study was approved by the institutional review board and complied with HIPAA regulations. Twenty-three patients with MTBI who had posttraumatic symptoms shortly after injury (<2 months) and 18 age-matched healthy control subjects were included in this study. Resting-state functional magnetic resonance imaging was performed at 3 T to characterize the DMN by using ICA methods, including a single-participant ICA on the basis of a comprehensive template from core seeds in the posterior cingulate cortex (PCC) and medial prefrontal cortex (MPFC) nodes. ICA z images of DMN components were compared between the two groups and correlated with neurocognitive tests and clinical performance in patients by using Pearson and Spearman rank correlation. Results: When compared with the control subjects, there was significantly reduced connectivity in the PCC and parietal regions and increased frontal connectivity around the MPFC in patients with MTBI (P < .01). These frontoposterior opposing changes within the DMN were significantly correlated (r = -0.44, P = .03). The reduced posterior connectivity correlated positively with neurocognitive dysfunction (eg, cognitive flexibility), while the increased frontal connectivity correlated negatively with posttraumatic symptoms (ie, depression, anxiety, fatigue, and postconcussion syndrome). Conclusion: These results showed abnormal DMN connectivity patterns in patients with MTBI, which may provide insight into how neuronal communication and information integration are disrupted among DMN key structures after mild head injury. (c) RSNA, 2012.

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

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.

Conventional imaging is unable to detect damage that accounts for permanent cognitive impairment in patients with mild traumatic brain injury (MTBI). While diffusion tensor imaging (DTI) can help to detect diffuse axonal injury (DAI), it is a limited indicator of tissue complexity. It has also been suggested that the thalamus may play an important role in the development of clinical sequelae in MTBI. The purpose of this study was to determine if diffusional kurtosis imaging (DKI), a novel quantitative magnetic resonance imaging (MRI) technique, can provide early detection of damage in the thalamus and white matter (WM) of MTBI patients and if thalamic injury is associated with cognitive impairment. Twenty-two MTBI patients and 14 controls underwent MRI and neuropsychological testing. Mean kurtosis (MK), fractional anisotropy (FA), and mean diffusivity (MD) were measured in the thalamus and several WM regions classically identified with DAI. Compared to controls, patients examined within one year after injury exhibited variously altered DTI and DKI derived measures in the thalamus and the internal capsule while, in addition to these regions, patients examined more than one year after injury also showed similar differences in the splenium of the corpus callosum and the centrum semiovale. Cognitive impairment was correlated to MK in the thalamus and the internal capsule. These findings suggest that combined use of DTI and DKI provides a more sensitive tool for identifying brain injury. In addition, MK in the thalamus might be useful for early prediction of permanent brain damage and cognitive outcome

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)