Denise A. Reyes

Longitudinal 1H MRS changes in mild cognitive impairment and Alzheimer’s disease

Magnetic resonance (MR)-based volume measurements of atrophy are potential markers of disease progression in patients with amnestic mild cognitive impairment (MCI) and Alzheimers disease (AD). Longitudinal changes in (1)H MR spectroscopy ((1)H MRS) metabolite markers have not been characterized in MCI subjects. Our objective was to determine the longitudinal (1)H MRS metabolite changes in patients with MCI, and AD, and to compare (1)H MRS metabolite ratios and ventricular volumes in tracking clinical disease progression in AD. The neuronal integrity marker N-acetylaspartate/creatine ratio declined in MCI and AD patients compared to cognitively normal elderly. The change in (1)H MRS metabolite ratios correlated with clinical progression about as strongly as the rate of ventricular expansion, suggesting that (1)H MRS metabolite ratios may be useful markers for the progression of AD. Choline/creatine ratio declined in stable MCI, compared to converter MCI patients and cognitively normal elderly, which may be related to a compensatory mechanism in MCI patients who did not to progress to AD.

In Vivo Magnetic Resonance Microimaging of Individual Amyloid Plaques in Alzheimer's Transgenic Mice

The ability to detect individual Alzheimers amyloid plaques in vivo by magnetic resonance microimaging (MRI) should improve diagnosis and also accelerate discovery of effective therapeutic agents for Alzheimers 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 μm in diameter can be detected in AD mice as young as 3 months of age with ex vivo MRI. Plaques 35 μm in diameter can be detected by 9 months of age with in vivo MRI. In vivo MRI of individual Alzheimers 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.

Magnetic Resonance Imaging of Alzheimer's Pathology in the Brains of Living Transgenic Mice: A New Tool in Alzheimer's Disease Research

Alzheimers 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 μm 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 1H magnetic resonance spectroscopy (1H 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.

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

Our goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, flouro‐deoxyglucose (FDG) PET, and MRI cortical thickness.

Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings

In a cross-sectional imaging study of 1331 cognitively non-impaired subjects aged 50–89, Jack et al. assess the consequences of defining neurodegeneration in five different ways on demographic associations with neurodegeneration, and on amyloidosis and neurodegeneration biomarker status by age. Different neurodegeneration measures provide similar but not completely redundant information.

Ante mortem amyloid imaging and β-amyloid pathology in a case with dementia with Lewy bodies

The association between ante mortem [(11)C]-Pittsburgh Compound B (PiB) retention and β-amyloid (Aβ) 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 Alzheimers disease by NIA-Reagan criteria. Sections from regions of interest (ROI) on post-mortem examination were studied. A significant correlation was found between cortical Aβ 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 Aβ density, but cannot differentiate neuritic from diffuse amyloid plaques in this case with DLB.

Comparison of amyloid plaque contrast generated by T2-weighted, T2*-weighted, and susceptibility-weighted imaging methods in transgenic mouse models of Alzheimer's disease.

One of the hallmark pathologies of Alzheimers disease (AD) is amyloid plaque deposition. Plaques appear hypointense on T2‐weighted and T  2* ‐weighted MR images probably due to the presence of endogenous iron, but no quantitative comparison of various imaging techniques has been reported. We estimated the T1, T2, T  2* , and proton density values of cortical plaques and normal cortical tissue and analyzed the plaque contrast generated by a collection of T2‐weighted, T  2* ‐weighted, and susceptibility‐weighted imaging (SWI) methods in ex vivo transgenic mouse specimens. The proton density and T1 values were similar for both cortical plaques and normal cortical tissue. The T2 and T  2* values were similar in cortical plaques, which indicates that the iron content of cortical plaques may not be as large as previously thought. Ex vivo plaque contrast was increased compared to a previously reported spin‐echo sequence by summing multiple echoes and by performing SWI; however, gradient echo and SWI were found to be impractical for in vivo imaging due to susceptibility interface–related signal loss in the cortex. Magn Reson Med, 2009.

Regional differences in MRI detection of amyloid plaques in AD transgenic mouse brain

Our laboratory and others have reported the ability to detect individual Alzheimers disease (AD) amyloid plaques in transgenic mouse brain in vivo by magnetic resonance imaging (MRI). Since amyloid plaques contain iron, most MRI studies attempting to detect plaques in AD transgenic mouse brain have employed techniques that exploit the paramagnetic effect of iron and have had mixed results. In the present study, using five-way anatomic spatial coregistration of MR images with three different histological techniques, properties of amyloid plaques in AD transgenic mouse brain were revealed that may explain their variable visibility in gradient- and spin-echo MR images. The results demonstrate differences in the visibility of plaques in the cortex and hippocampus, compared to plaques in the thalamus, by the different MRI sequences. All plaques were equally detectable by T(2)SE, while only thalamic plaques were reliably detectable by T(2)*GE pulse sequences. Histology revealed that cortical/hippocampal plaques have low levels of iron while thalamic plaques have very high levels. However, the paramagnetic effect of iron does not appear to be the sole factor leading to the rapid decay of transverse magnetization (short T(2)) in cortical/hippocampal plaques. Accordingly, MRI methods that rely less on iron magnetic susceptibility effect may be more successful for eventual human AD plaque MR imaging, particularly since human AD plaques more closely resemble the cortical and hippocampal plaques of AD transgenic mice than thalamic plaques.

Effects of MRI scan acceleration on brain volume measurement consistency

To evaluate the effects of recent advances in magnetic resonance imaging (MRI) radiofrequency (RF) coil and parallel imaging technology on brain volume measurement consistency.

Micro-CT scanner with a focusing polycapillary x-ray optic

A bench-top x-ray micro-CT scanner was used to evaluate a focusing x-ray optic as a means to augment micro-CT scanner performance. The optic consists of a bundle of hollow glass fibers (25 micrometer diameter) which are arranged and curved so that the optic has an 8 degree input focus and a 4.1 degree output focus cone angle. This optic was placed between our spectroscopy x-ray source (18 keV) and the specimen. The x-ray fluorescent crystal plate was placed as close as possible behind the specimen and the light image generated within it was projected onto a CCD with a lens. The specimen was imaged and rotated about its axis in 1 degree steps until a 360 degree rotation was completed. The resulting, normalized, projection images were submitted to modified Feldkamp cone- beam reconstruction. A 1 cm diameter plastic cylinder, in which glass microspheres (nominally 10, 30, 100 or 300 micrometer diameter) were suspended, was used to compare the spatial resolution of the x-ray optic versus the no-optic scans performed at a range of comparable focal spot-to- specimen distances. The increased flux at the specimen obtained by placing the specimen (and fluorescent crystal) closer to the output focal spot of the optic resulted in increased x-ray flux, thereby reducing scan duration several- fold without increase in penumbral blurring.