Faculty Bibliography

The accumulation of amyloid-beta (Abeta) plaques is a central feature of Alzheimer's disease (AD). First reported in animal models, it remains uncertain if peripheral inflammatory and/or infectious conditions in humans can promote Abeta brain accumulation. Periodontal disease, a common chronic infection, has been previously reported to be associated with AD. Thirty-eight cognitively normal, healthy, and community-residing elderly (mean age, 61 and 68% female) were examined in an Alzheimer's Disease Research Center and a University-Based Dental School. Linear regression models (adjusted for age, apolipoprotein E, and smoking) were used to test the hypothesis that periodontal disease assessed by clinical attachment loss was associated with brain Abeta load using 11C-Pittsburgh compound B (PIB) positron emission tomography imaging. After adjusting for confounders, clinical attachment loss (>/=3 mm), representing a history of periodontal inflammatory/infectious burden, was associated with increased PIB uptake in Abeta vulnerable brain regions (p = 0.002). We show for the first time in humans an association between periodontal disease and brain Abeta load. These data are consistent with the previous animal studies showing that peripheral inflammation/infections are sufficient to produce brain Abeta accumulations.

PURPOSE: To explore associations of whole-lesion histogram diffusion metrics with pathologic findings and subsequent metastatic disease in bladder cancer patients undergoing radical cystectomy. METHODS: Twenty-three bladder cancer patients (21M, 2F; mean 70 +/- 11 years) underwent MRI before cystectomy. A volume-of-interest was placed on all slices on the ADC map encompassing each lesion. Whole-lesion mean, kurtosis, and skewness of ADC were calculated and compared with T stage and pelvic nodal status at cystectomy and with subsequent metastasis in 20/25 patients with available follow-up. RESULTS: At cystectomy, 39 % (9/23) were stage T2, 61 % (14/23) >/=T3, and 28 % (5/23) exhibited positive nodes; 35 % (7/20) developed later metastases. Mean ADC was significantly lower in stage >/=T3 than in lower stage tumors (1.20 +/- 0.36 x 10-3 vs. 1.55 +/- 0.36 x 10-3 mm2/s; p = 0.044), but showed no association with nodal or metastatic disease (p = 0.362-0.709). Kurtosis was significantly lower in tumors with, compared to without, nodal disease (-0.05 +/- 0.29 vs. 0.91 +/- 1.16; p = 0.037), and showed a non-significant decrease in tumors with, compared to without, later metastases (0.23 +/- 0.63 vs. 0.83 +/- 0.89; p = 0.088). Kurtosis was not associated with T stage (p = 0.811), and skew was not associated with any outcome (p = 0.516-0.643). Mean ADC achieved highest AUC for identification of stage >/=T3 (AUC = 0.754 vs. 0.516-0.643 for other metrics). Kurtosis achieved highest AUC for nodal disease (AUC = 0.811 vs. 0.522-0.556 for other metrics) and metastases (AUC = 0.736 vs. 0.516-0.626 for other metrics). Only difference in AUC between skewness and kurtosis for nodal disease was significant (p = 0.031). CONCLUSION: While requiring larger studies, kurtosis has potential to complement mean ADC in bladder cancer prognosis using whole-lesion histogram analysis.

INTRODUCTION: Neurofibrillary tau pathology and amyloid beta (Abeta) plaques, characteristic lesions of Alzheimer's disease (AD), show different neocortical laminar distributions. NFT-tau pathology tends to be located closer to the gray-white-matter boundary (G-WB) whereas Abeta is dispersed throughout the width of the cortical ribbon. METHODS: Using PET radiotracers for tau and Abeta lesions, we developed an image analysis tool to measure the distance of tracer-positive voxels to the G-WB. We studied 5 AD and 5 healthy subjects with both 18F-THK5117 (tau) and 11C-PiB (Abeta) PET. RESULTS: We observed that on average tau positive-voxels were closer to the white matter than the Abeta positive voxels. This effect was found for all AD subjects and for all regions, both before and after regionally adjusting for the non-specific white matter binding of both tracers. The differential laminar pattern was validated at post mortem. CONCLUSION: Within cortical lamina distance measures may be of value in testing PET tracers for their anatomical selectivity.

PURPOSE: The purpose of this study was to estimate perfusion metrics in healthy and cirrhotic liver with pharmacokinetic modeling of high-temporal resolution reconstruction of continuously acquired free-breathing gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced acquisition in patients undergoing clinically indicated liver magnetic resonance imaging. SUBJECTS AND METHODS: In this Health Insurance Portability and Accountability Act-compliant prospective study, 9 cirrhotic and 10 noncirrhotic patients underwent clinical magnetic resonance imaging, which included continuously acquired radial stack-of-stars 3-dimensional gradient recalled echo sequence with golden-angle ordering scheme in free breathing during contrast injection. A total of 1904 radial spokes were acquired continuously in 318 to 340 seconds. High-temporal resolution data sets were formed by grouping 13 spokes per frame for temporal resolution of 2.2 to 2.4 seconds, which were reconstructed using the golden-angle radial sparse parallel technique that combines compressed sensing and parallel imaging. High-temporal resolution reconstructions were evaluated by a board-certified radiologist to generate gadolinium concentration-time curves in the aorta (arterial input function), portal vein (venous input function), and liver, which were fitted to dual-input dual-compartment model to estimate liver perfusion metrics that were compared between cirrhotic and noncirrhotic livers. RESULTS: The cirrhotic livers had significantly lower total plasma flow (70.1 +/- 10.1 versus 103.1 +/- 24.3 mL/min per 100 mL; P < 0.05), lower portal venous flow (33.4 +/- 17.7 versus 89.9 +/- 20.8 mL/min per 100 mL; P < 0.05), and higher arterial perfusion fraction (52.0% +/- 23.4% versus 12.4% +/- 7.1%; P < 0.05). The mean transit time was higher in the cirrhotic livers (24.4 +/- 4.7 versus 15.7 +/- 3.4 seconds; P < 0.05), and the hepatocellular uptake rate was lower (3.03 +/- 2.1 versus 6.53 +/- 2.4 100/min; P < 0.05). CONCLUSIONS: Liver perfusion metrics can be estimated from free-breathing dynamic acquisition performed for every clinical examination without additional contrast injection or time. This is a novel paradigm for dynamic liver imaging.

PURPOSE: To evaluate the precision of measures of bone volume and bone volume fraction derived from high-resolution 3T MRI of proximal femur bone microarchitecture using non-uniformity correction. METHODS: This HIPAA compliant, institutional review board approved study was conducted on six volunteers (mean age [Formula: see text] years), and written informed consent was obtained. All volunteers underwent a 3T FLASH MRI hip scan at three time points: baseline, second scan same day (intra-scans), and third scan one week later (inter-scans). Segmentation of femur images and values for total proximal femur volume ([Formula: see text]), bone volume ([Formula: see text]), and bone volume fraction (BVF) were calculated using in-house developed software, FireVoxel. Two types of non-uniformity corrections were applied to images (N3 and BiCal). Precision values were calculated using absolute percent error (APE). Statistical analysis was carried out using one-sample one-sided t test to observe the consistency of the precision and paired t test to compare between the various methods and scans. RESULTS: No significant differences in bone volume measurements were observed for intra- and inter-scans. When using non-uniformity correction and assessing all subjects uniformly at the level of the lesser trochanter, precision values overall improved, especially significantly ([Formula: see text]) when measuring bone volume, [Formula: see text]. [Formula: see text] values using the combination of N3 or BiCal with CLT had a significant consistent APE values of less than 2.5 %, while BVF values were all consistently and significantly lower than 2.5 % APE. CONCLUSION: Our results demonstrate the precision of high-resolution 3D MRI measures were comparable to that of dual-energy X-ray absorptiometry. Additional corrections to the analysis technique by cropping at the lesser trochanter or using non-uniformity corrections helped to improve precision. The high precision values from these MRI scans provide evidence for MRI of the proximal femur as a promising tool for osteoporosis diagnosis and treatment.

PURPOSE: One of the interesting features of the amyloid tracer Pittsburgh compound B (PiB) is that it generates a signal in the white matter (WM) in both healthy subjects and cognitively impaired individuals. This characteristic gave rise to the possibility that PiB could be used to trace WM pathology. In a group of cognitively healthy elderly we examined PiB retention in normal-appearing WM (NAWM) and WM lesions (WML), one of the most common brain pathologies in aging. METHODS: We segmented WML and NAWM on fluid attenuation inversion recovery (FLAIR) images of 73 subjects (age 61.9 +/- 10.0, 71 % women). PiB PET images were corrected for partial volume effects and coregistered to FLAIR images and WM masks. WML and NAWM PiB signals were then extracted. RESULTS: PiB retention in WML was lower than in NAWM (p < 0.001, 14.6 % reduction). This was true both for periventricular WML (p < 0.001, 17.8 % reduction) and deep WML (p = 0.001, 7.5 % reduction). CONCLUSION: PiB binding in WM is influenced by the presence of WML, which lower the signal. Our findings add to the growing evidence that PiB can depict WM pathology and should prompt further investigations into PiB binding targets in WM.

Cerebral perfusion was evaluated in 87 subjects prospectively enrolled in three study groups-healthy controls (HC), patients with insulin resistance (IR) but not with diabetes, and type 2 diabetes mellitus (T2DM). Participants received a comprehensive 8-hour clinical evaluation and arterial spin labeling magnetic resonance imaging (MRI). In order of decreasing significance, an association was found between cerebral blood flow (CBF) and sex, waist circumference, diastolic blood pressure (BP), end tidal CO2, and verbal fluency score (R2=0.27, F=5.89, P<0.001). Mean gray-matter CBF in IR was 4.4 mL/100 g per minute lower than in control subjects (P=0.005), with no hypoperfusion in T2DM (P=0.312). Subjects with IR also showed no CO2 relationship (slope=-0.012) in the normocapnic range, in contrast to a strong relationship in healthy brains (slope=0.800) and intermediate response (slope=0.445) in diabetic patients. Since the majority of T2DM but few IR subjects were aggressively treated with blood glucose, cholesterol, and BP lowering medications, our finding could be attributed to the beneficial effect of these drugs.Journal of Cerebral Blood Flow & Metabolism advance online publication, 15 October 2014; doi:10.1038/jcbfm.2014.173.

Background: Mild cognitive impairment (MCI) is an intermediary state on the way to Alzheimer's disease (AD). Little is known about whole brain concentration of the neuronal marker, N-acetylaspartate (NAA) in MCI patients. Objective: To test the hypothesis that since MCI and AD are both neurodegenerative, quantification of the NAA in their whole brain (WBNAA) could differentiate them from cognitively-intact matched controls. Methods: Proton MR spectroscopy to quantify the WBNAA was applied to 197 subjects (86 females) 72.6 +/- 8.4 years old (mean +/- standard deviation). Of these, 102 were cognitively intact, 42 diagnosed as MCI, and 53 as probable AD. Their WBNAA amounts were converted into absolute concentration by dividing with the brain volume segmented from the MRI that also yielded the fractional brain volume (fBPV), an atrophy metric. Results: WBNAA concentration of MCI and AD patients (10.5 +/- 3.0 and 10.1 +/- 2.9 mM) were not significantly different (p = 0.85). They were, however, highly significantly 25-29% lower than the 14.1 +/- 2.4 mM of normal matched controls (p < 10-4). The fBPV of MCI and AD patients (72.9 +/- 4.9 and 69.9 +/- 4.7%) differed significantly from each other (4%, p = 0.02) and both were significantly lower than the 74.6 +/- 4.4% of normal elderly (2%, p = 0.003 for MCI; 6%, p < 10-4 for AD). ROC curve analysis has shown WBNAA to have 70.5% sensitivity and 84.3% specificity to differentiate MCI or AD patients from normal elderly versus just 68.4 and 65.7% for fBPV. Conclusion: Low WBNAA in MCI patients compared with cognitively normal contemporaries may indicate early neuronal damage accumulation and supports the notion of MCI as an early stage of AD. It also suggests WBNAA as a potential marker of early AD pathology.