Faculty Bibliography

Accumulation of toxic protein aggregates-amyloid-beta (Abeta) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Abeta accumulation has been hypothesized to result from an imbalance between Abeta production and clearance; indeed, Abeta clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Abeta is cleared from the brain. Extracellular Abeta deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Abeta (eAbeta) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAbeta from the brain, any alteration to their function could contribute to AD. An understanding of Abeta clearance might provide strategies to reduce excess Abeta deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Abeta.

PURPOSE: To compare boundaries of prostate tumors on MRI and histologic assessment from radical prostatectomy (RP) using detailed software-assisted co-registration, in order to define an optimal treatment margin to achieve complete tumor destruction during image-guided focal ablation. METHODS: 33 patients who underwent 3T MRI before RP were included. A radiologist traced lesion borders on MRI and assigned a suspicion score (SS) from 2-5. 3D reconstructions were created from high-resolution digitalized slides from RP specimens and co-registered to MRI using advanced software. Tumors were compared between histology and MRI using the Hausdorff Distance (HD) and stratified by MRI-SS, Gleason Score (GS), and lesion diameter. Cylindrical volume estimates of treatment effects were used to define the optimal treatment margin. RESULTS: 46 histologically confirmed cancers underwent 3D software-based registration with MRI. MRI underestimated tumor sizes, with the maximal discrepancy between MRI and histologic boundaries for a given tumor averaging 1.99+/-3.1mm (18.5% of the MRI diameter). Boundary underestimation was larger for MRI-SS>/=4 lesions (+3.49+/-2.1mm; p<0.001) and GS>/=7 lesions (+2.48+/-2.8mm; p 0.035). On average, a simulated cylindrical treatment volume based on the MRI boundary missed 14.8% of the tumor volume compared with a simulated cylindrical volume based on the histologic boundary. A simulated treatment volume based on a 9mm treatment margin achieved complete histologic tumor destruction in 100% of patients. CONCLUSION: MRI underestimates histologically-determined tumor boundaries, especially for high MRI-SS and high GS lesions. A 9mm treatment margin around an MRI-visible lesion consistently ensures treatment of the entire histologic tumor volume during focal ablative therapy.

INTRODUCTION: Osteoporosis is a disease of weak bone. Our goal was to determine the measurement reproducibility of magnetic resonance assessment of proximal femur strength. METHODS: This study had institutional review board approval, and written informed consent was obtained from all subjects. We obtained images of proximal femur microarchitecture by scanning 12 subjects three times within 1 week at 3T using a high-resolution 3-D FLASH sequence. We applied finite element analysis to compute proximal femur stiffness and femoral neck elastic modulus. RESULTS: Within-day and between-day root-mean-square coefficients of variation and intraclass correlation coefficients ranged from 3.5 to 6.6 % and 0.96 to 0.98, respectively. CONCLUSION: The measurement reproducibility of magnetic resonance assessment of proximal femur strength is suitable for clinical studies of disease progression or treatment response related to osteoporosis bone-strengthening interventions.

Background: The association of blood pressure (BP) and dementia in the elderly is debated. Whereas hypertension in mid-life appears to increase the risk of Alzheimer's dementia (AD); lower BP in the elderly is associated with a greater risk of cognitive decline. White matter lesions (WML) are the result of impaired cerebral blood flow, possibly due to insufficient perfusion pressure. The hippocampus, an early site of AD pathology, is also among the brain structures most sensitive to hypoperfusion. We tested the hypothesis that elderly normotensive subjects with WML represent a group suffering from subclinical cerebral hypoperfusion, which increases their risk for AD. We examined 24-hour ambulatory blood pressure (ABP), hippocampal volume and memory in four groups of subjects: hypertensive (HTN+) and normotensive (HTN-) subjects with (WML+) and without (WML-) white matter changes. Methods: Sixty-six subjects (mean age 72.63 6 8.48, 62% female) underwent a thorough medical assessment, brain magnetic resonance imaging (MRI), 24 hour ABP monitoring, and memory testing. Fluid attenuated inversion recovery images were used to determine the WML using the Fazekas scale. Periventricular (PWML) and deep white matter lesions (DWML) were graded separately and summed to create the total load. High load (WML+) was defined as a total load >3. Brain volumes were obtained from T1- weighted MRI images using FreeSurfer. Memory tests were converted to age, education and gender adjusted standardized scores. HTN was determined based on antihypertensive medication use and the results of 24 h APBM. Results: Groups differed in age, but not in education or gender (Table 1). HTNWML+ group had the lowest mean systolic BP (F=43.0, p<.001), and the lowest mean awake systolic BP (F=45.0, p<.001) (Table 1). Post hoc contrast analyses showed that hippocampal volumes, but not whole brain volumes, decreased linearly from HTN-WML-, through HTN+WML- and HTN+WML+, to HTN-WML+ group (p=.006) (for the entire model F=2.7, p=.049) (Figure 1). Memory scores showed a similar trend (p=.10) (for the entire model F=1.9, p=.10) (Figure 2). Conclusions: Normotensive elderly with WML have lower BP, lower hippocampal volumes and poorer memory overall. This constellation of clinical and imaging characteristics may increase their risk of developing AD. (Figure Presented)

Background: Metabolic syndrome (MetS) is a multiplex risk factor for cardiovascular disease that deserves significant attention. While there is a growing recognition of the link between MetS and cognition, little is known about how MetS relates to cortical amyloid deposition. The detection of vascular risk is commonly followed by an introduction of appropriate treatment aimed at risk modification. The treatment itself may affect accumulation of brain amyloid, but this issue is largely unknown. Our aim was to assess the relationships between MetS, antihypertensive and antilipid medications, and cortical amyloid binging of Pittsburgh compound B (PiB) in cognitively healthy adults and elderly. Methods: A crosssectional study of subjects (n=155) participating in studies of brain aging who underwent Positron Emission Tomography (PET) imaging with PiB. Sixty-seven percent were women, mean age of the entire group was 60.4+/-10.5 years, mean education 16.6+/-2.0 years. General linear models were used to compare groups. Predictors of cortical amyloid accumulation were tested with linear regression models. Tested predictors included MetS, visceral obesity, blood pressure, glucose, HDL and triglycerides levels, treatment with angiotensin receptor blockers (ARBs), beta-blockers, diuretics, angiotensin converting enzymes inhibitor, statins, antidepressants, demographics, and ApoE 4 carrier status. Results: After accounting for age and the treatment with antidepressants, the use of ARBs (b=-.15, p=.048) and diuretics (b=-.28, p=.001) predicted less amyloid accumulation, while statins (b=.19, p=.015) were the related to more cortical amyloid deposition. Although MetS was not related to amyloid deposition, central obesity was associated with greater cortical amyloid in women irrespective of medication status. Conclusions: ARBs and diuretics were associated with less amyloid deposition. Prospective studies should confirm this benefit of antihypertensive drugs and establish whether such modifications translate into measurable clinical outcomes. Women may be particularly sensitive to detrimental effects of obesity on the aging brain. This must be taken into consideration while planning future interventions

OBJECTIVE: The purpose of this article was to assess the feasibility of golden-angle radial acquisition with compress sensing reconstruction (Golden-angle RAdial Sparse Parallel [GRASP]) for acquiring high temporal resolution data for pharmacokinetic modeling while maintaining high image quality in patients with Crohn disease terminal ileitis. MATERIALS AND METHODS: Fourteen patients with biopsy-proven Crohn terminal ileitis were scanned using both contrast-enhanced GRASP and Cartesian breath-hold (volume-interpolated breath-hold examination [VIBE]) acquisitions. GRASP data were reconstructed with 2.4-second temporal resolution and fitted to the generalized kinetic model using an individualized arterial input function to derive the volume transfer coefficient (K(trans)) and interstitial volume (ve). Reconstructions, including data from the entire GRASP acquisition and Cartesian VIBE acquisitions, were rated for image quality, artifact, and detection of typical Crohn ileitis features. RESULTS: Inflamed loops of ileum had significantly higher K(trans) (3.36 +/- 2.49 vs 0.86 +/- 0.49 min(-1), p < 0.005) and ve (0.53 +/- 0.15 vs 0.20 +/- 0.11, p < 0.005) compared with normal bowel loops. There were no significant differences between GRASP and Cartesian VIBE for overall image quality (p = 0.180) or detection of Crohn ileitis features, although streak artifact was worse with the GRASP acquisition (p = 0.001). CONCLUSION: High temporal resolution data for pharmacokinetic modeling and high spatial resolution data for morphologic image analysis can be achieved in the same acquisition using GRASP.

PURPOSE: We used a combined intravoxel incoherent motion-diffusion tensor imaging (IVIM-DTI) methodology to distinguish structural from flow effects on renal diffusion anisotropy. METHODS: Eight volunteers were examined with IVIM-DTI at 3T with 20 diffusion directions and 10 b-values. Mean diffusivity (MD) and fractional anisotropy (FA) from DTI analysis were calculated for low (b 200 s/mm2 ), and full b-value ranges. IVIM-parameters perfusion-fraction fP , pseudo-diffusivity Dp , and tissue-diffusivity Dt were first calculated independently on a voxelwise basis for all directions. After estimating a fixed isotropic fp from these data, global anisotropies of Dt and Dp in the cortex and medulla were determined in a constrained cylindrical description and visualized using polar plots and cosine scatterplots. RESULTS: For all b-value ranges, medullary FA was significantly higher than that of the cortex. The corticomedullary difference was smaller for the high b-value range. Significantly higher fp and Dt were determined for the cortex and showed a significantly higher directional variance in the medulla. Polar plot analysis displayed nearly isotropic Dp and Dt in the cortex and anisotropy in the medulla. CONCLUSION: Both flow and microstructure apparently contribute to the medullary diffusion anisotropy. The described novel method may be useful in separating decreased tubular flow from irreversible structural tubular damage, for example, in diabetic nephropathy or during allograft rejection. Magn Reson Med, 2014. (c) 2014 Wiley Periodicals, Inc.

PURPOSE: To retrospectively assess the utility of whole-lesion apparent diffusion coefficient (ADC) metrics in characterizing the Gleason 4 component of Gleason 7 prostate cancer (PCa) at radical prostatectomy. MATERIALS AND METHODS: Seventy patients underwent phased-array coil 3T-magnetic resonance imaging (MRI) before prostatectomy. A uropathologist mapped locations and Gleason 4 percentage (G4%) of Gleason 7 tumors. Two radiologists independently reviewed ADC maps, aware of tumor locations but not G4%, and placed a volume-of-interest (VOI) on all slices including each lesion on the ADC map to obtain whole-lesion mean ADC and ADC entropy. Entropy reflects textural variation and increases with greater macroscopic heterogeneity. Performance for characterizing Gleason 7 tumors was assessed with mixed-model analysis of variance (ANOVA) and logistic regression. RESULTS: Among 84 Gleason 7 tumors (G4% 5%-85%, median 30%; 59 Gleason 3+4, 25 Gleason 4+3), ADC entropy was significantly higher in Gleason 4+3 than Gleason 3+4 tumors (R1: 5.27 +/- 0.61 vs. 4.62 +/- 0.78, P = 0.001; R2: 5.91 +/- 0.32 vs. 5.57 +/- 0.56, P = 0.004); mean ADC was not significantly different between these groups (R1: 0.90 +/- 0.15*10-3 cm2 /s vs. 0.98 +/- 0.21*10-3 cm2 /s, P = 0.075; R2: 1.06 +/- 0.19*10-3 cm2 /s vs. 1.14 +/- 0.16*10-3 cm2 /s, P = 0.083). The area under the receiver operating characteristic (ROC) curve (AUC) for differentiating groups was significantly higher with ADC entropy than mean ADC for one observer (R1: 0.74 vs. 0.57, P = 0.027; R2: 0.69 vs. 0.61, P = 0.329). For R1, correlation with G4% was moderate for ADC entropy (r = 0.45) and weak for mean ADC (r = -0.25). For R2, correlation with G4% was moderate for ADC entropy (r = 0.41) and mean ADC (r = -0.32). For both readers, ADC entropy (P = 0.028-0.003), but not mean ADC (P = 0.384-0.854), was a significant independent predictor of G4%. CONCLUSION: Whole-lesion ADC entropy outperformed mean ADC in characterizing Gleason 7 tumors and may help refine prognosis for this heterogeneous PCa subset. J. Magn. Reson. Imaging 2014. (c) 2014 Wiley Periodicals, Inc.