Defining imaging biomarker cut points for brain aging and Alzheimer's disease.

INTRODUCTION: Our goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, flouro-deoxyglucose (FDG) PET, and MRI cortical thickness. METHODS: We examined five methods for determining cut points. RESULTS: The reliable worsening method produced a cut point only for amyloid PET. The specificity, sensitivity, and accuracy of cognitively impaired versus young clinically normal (CN) methods labeled the most people abnormal and all gave similar cut points for tau PET, FDG PET, and cortical thickness. Cut points defined using the accuracy of cognitively impaired versus age-matched CN method labeled fewer people abnormal. DISCUSSION: In the future, we will use a single cut point for amyloid PET (standardized uptake value ratio, 1.42; centiloid, 19) based on the reliable worsening cut point method. We will base lenient cut points for tau PET, FDG PET, and cortical thickness on the accuracy of cognitively impaired versus young CN method and base conservative cut points on the accuracy of cognitively impaired versus age-matched CN method.

Effects of MRI scan acceleration on brain volume measurement consistency.

PURPOSE: To evaluate the effects of recent advances in magnetic resonance imaging (MRI) radiofrequency (RF) coil and parallel imaging technology on brain volume measurement consistency. MATERIALS AND METHODS: In all, 103 whole-brain MRI volumes were acquired at a clinical 3T MRI, equipped with a 12- and 32-channel head coil, using the T1-weighted protocol as employed in the Alzheimer's Disease Neuroimaging Initiative study with parallel imaging accelerations ranging from 1 to 5. An experienced reader performed qualitative ratings of the images. For quantitative analysis, differences in composite width (CW, a measure of image similarity) and boundary shift integral (BSI, a measure of whole-brain atrophy) were calculated. RESULTS: Intra- and intersession comparisons of CW and BSI measures from scans with equal acceleration demonstrated excellent scan-rescan accuracy, even at the highest acceleration applied. Pairs-of-scans acquired with different accelerations exhibited poor scan-rescan consistency only when differences in the acceleration factor were maximized. A change in the coil hardware between compared scans was found to bias the BSI measure. CONCLUSION: The most important findings are that the accelerated acquisitions appear to be compatible with the assessment of high-quality quantitative information and that for highest scan-rescan accuracy in serial scans the acquisition protocol should be kept as consistent as possible over time.

Aortic Stiffness and White Matter Microstructural Integrity Assessed by Diffusion Tensor Imaging: The ARIC-NCS.

Background Changes in white matter microstructural integrity are detectable before appearance of white matter lesions on magnetic resonance imaging as a manifestation of cerebral small-vessel disease. The information relating poor white matter microstructural integrity to aortic stiffness, a hallmark of aging, is limited. We aimed to examine the association between aortic stiffness and white matter microstructural integrity among older adults. Methods and Results We conducted a cross-sectional study to examine the association between aortic stiffness and white matter microstructural integrity among 1484 men and women (mean age, 76 years) at the 2011 to 2013 examination of the ARIC-NCS (Atherosclerosis Risk in Communities Neurocognitive Study). Aortic stiffness was measured as carotid-femoral pulse wave velocity. Cerebral white matter microstructural integrity was measured as fractional anisotropy and mean diffusivity using diffusion tensor imaging. Multivariable linear regression was used to examine the associations of carotid-femoral pulse wave velocity with fractional anisotropy and mean diffusivity of the overall cerebrum and at regions of interest. Each 1-m/s higher carotid-femoral pulse wave velocity was associated with lower overall fractional anisotropy (ß=-0.03; 95% CI, -0.05 to -0.02) and higher overall mean diffusivity (ß=0.03; 95% CI, 0.02-0.04). High carotid-femoral pulse wave velocity (upper 25th percentile) was associated with lower fractional anisotropy (ß=-0.40; 95% CI, -0.61 to -0.20) and higher overall mean diffusivity (ß=0.27; 95% CI, 0.10-0.43). Similar associations were observed at individual regions of interest. Conclusions High aortic stiffness is associated with low cerebral white matter microstructural integrity among older adults. Aortic stiffness may serve as a target for the prevention of poor cerebral white matter microstructural integrity.

Magnetic resonance imaging of Alzheimer's pathology in the brains of living transgenic mice: a new tool in Alzheimer's disease research.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Cardinal pathologic features of AD are amyloid plaques and neurofibrillary tangles, and most in the field believe that the initiating events ultimately leading to clinical AD center on disordered metabolism of amyloid beta protein. Mouse models of AD have been created by inserting one or more human mutations associated with disordered amyloid metabolism and that cause early onset familial AD into the mouse genome. Human-like amyloid plaque formation increases dramatically with age in these transgenic mice. Amyloid reduction in humans is a major therapeutic objective, and AD transgenic mice allow controlled study of this biology. Recent work has shown that amyloid plaques as small as 35 microm can be detected using in vivo magnetic resonance microimaging (MRMI) at high magnetic field (9.4 T). In addition, age-dependent changes in metabolite concentration analogous to those that have been identified in human AD patients can be detected in these transgenic mice using single-voxel (1)H magnetic resonance spectroscopy ((1)H MRS) at high magnetic field. These MR-based techniques provide a new set of tools to the scientific community engaged in studying the biology of AD in transgenic models of the disease. For example, an obvious application is evaluating therapeutic modification of disease progression. Toward the end of this review, the authors include results from a pilot study demonstrating feasibility of using MRMI to detect therapeutic modification of plaque progression in AD transgenic mice.

In vivo magnetic resonance microimaging of individual amyloid plaques in Alzheimer's transgenic mice.

The ability to detect individual Alzheimer's amyloid plaques in vivo by magnetic resonance microimaging (MRI) should improve diagnosis and also accelerate discovery of effective therapeutic agents for Alzheimer's disease (AD). Here, we perform in vivo and ex vivo MRI on double transgenic AD mice as well as wild-type mice at varying ages and correlate these with thioflavin-S and iron staining histology. Quantitative counts of individual plaques on MRI increase with age and correlate with histologically determined plaque burden. Plaques 20 microm in diameter can be detected in AD mice as young as 3 months of age with ex vivo MRI. Plaques 35 microm in diameter can be detected by 9 months of age with in vivo MRI. In vivo MRI of individual Alzheimer's amyloid plaques provides a noninvasive estimate of plaque burden in transgenic AD mice that might be useful in assessing the efficacy of amyloid reduction therapies.

Three-dimensional imaging of fractures in outlet struts of Björk-Shiley convexo-concave heart valves by microcomputed tomography in vitro.

BACKGROUND AND AIMS OF THE STUDY: For implanted Björk-Shiley convexo-concave (BSCC) heart valves, structural failure of the valve's U-shaped outlet strut results in embolization of its blood flow-regulating disc (occluder), with consequent patient morbidity and mortality. After a variable and unpredictable number of cardiac cycles, one strut leg may fatigue ('single-leg separation'; SLS); subsequently the other strut leg may also fatigue, resulting in full structural failure ('outlet strut failure'; OSF). Some BSCC valves are believed to be at more risk of SLS and OSF than others. As valves may function in the SLS condition for some time before OSF occurs, several investigators have sought non-invasive methods to differentiate valves with SLS struts from valves with intact struts in order to provide a rationale for prophylaxis. Herein, we report the use of X-ray microcomputed tomography (micro-CT) to image and characterize SLS strut fractures, including fracture faces otherwise visible only by means of physical sectioning. METHODS: An X-ray micro-CT system was adapted to provide high-resolution, three-dimensional (3D) images of intact and fractured BSCC valve outlet struts in vitro. System modifications included use of a tungsten anode X-ray source to achieve sufficiently high X-ray energies to overcome attenuation within the metal structures, and a hafnium filter to minimize the imaging artifact caused by X-ray beam hardening. For rotating the valve for tomographic scanning, special alignment procedures were developed to maintain the region of interest within the field of view. Typical 3D images of the outlet struts were composed of cubic voxels, 10 microm on a side. Image analysis and display software was used to view the outlet struts and the fractures from several perspectives, including en-face images of fracture surfaces. RESULTS: 3D volume data representations of the SLS and intact outlet struts were obtained, facilitating identification of fracture location and geometry. Enface images of the fracture surfaces were also generated. Several different fracture geometries were observed, such as fractures with and without longitudinal gaps between the fracture faces, and fractures with and without lateral displacement between the faces. En-face views showed varying degrees of roughness on fracture faces. CONCLUSION: This application of micro-CT to image outlet strut fractures in BSCC valve explants demonstrates the value of this method for fracture characterization in vitro, including visualization of fracture faces of SLS struts without physical sectioning. Although the method is not suitable for clinical use because it requires high-intensity X-rays, micro-CT can serve as a tool to understand further any failure mechanisms, and to aid the development of clinical differentiation methods.

Cryostatic micro-computed tomography imaging of arterial wall perfusion.

A double-walled copper vessel, 32 cc in volume, was fabricated for scanning tissue specimens while maintained below freezing point. To keep specimen temperature within +/- 1 degrees C, temperature sensors within the chamber control, the rate of inflow of the cold nitrogen gas vented through the chamber. The specimen is attached to a small platform on top of a vertical pin which is attached to the computer-controlled rotating stage under the vessel. The purpose of this arrangement is to permit scanning of specimens up to 2 cm3 that (1) cannot be "fixed" (e.g., with formalin) because of analyses which are incompatible with prior fixation (certain immunohistochemistry and biomolecular methods), or (2) are "snap"-frozen during a transient process, such as the accumulation and/or washout of radiopaque indicators. Examples of "cryoscans" of porcine carotid and coronary artery wall opacification in either untouched or acutely stented arteries, snap-frozen immediately after selective intra-arterial injection of a contrast agent, show accumulation of contrast in the extravascular space indicating increased endothelial permeability or endothelial and medial disruption following stent placement. The detection of contrast in the adventitia suggest that vasa vasorum deliver the contrast agent from the main lumen to the adventitial extravascular space but not to the media.

Antemortem amyloid imaging and ß-amyloid pathology in a case with dementia with Lewy bodies.

The association between ante mortem [(11)C]-Pittsburgh Compound B (PiB) retention and ß-amyloid (Aß) load, Lewy body (LB) and neurofibrillary tangle (NFT) densities were investigated in a pathologically confirmed case of dementia with Lewy bodies (DLB). A 76 year old man presenting with a clinical diagnosis of DLB had undergone PiB-positron emission tomography (PET), (18)F FDG-PET and magnetic resonance imaging (MRI) 18 months before death. The pathologic diagnosis was DLB neocortical-type with low-likelihood of Alzheimer's disease by NIA-Reagan criteria. Sections from regions of interest (ROI) on post-mortem examination were studied. A significant correlation was found between cortical Aß density and PiB retention in the 17 corresponding ROIs (r = 0.899; p < 0.0001). Bielschowsky silver stain revealed mostly sparse neocortical neuritic plaques, whereas diffuse plaques were frequent. There was no correlation between LB density and PiB retention (r = 0.13; p = 0.66); nor between NFT density and PiB retention (r = -0.36; p = 0.17). The ROI-based analysis of imaging and histopathological data confirms that PiB uptake on PET is a specific marker for Aß density, but cannot differentiate neuritic from diffuse amyloid plaques in this case with DLB.