Current Medical Imaging - Volume 7, Issue 1, 2011

Magnetic resonance imaging (MRI) plays an important role in research on Alzheimer's disease (AD). This includes studies in both transgenic mouse models as well as in humans. In this special hot topic issue in CMIR we aim to give an overview on “Prospects of Magnetic Resonance Imaging for Alzheimer's Disease”. This issue has been classified into three main sections based on the type of MRI methods exploited in the field of AD: (1) Structural MRI, (2) Vascular MRI and (3) MR spectroscopy. In this way the issue provides a comprehensive coverage of the applications of MRI for AD. STRUCTURAL MRI Using structural MRI methods, two types of information can be generated in AD in vivo: changes induced by specific histological hallmarks of AD (amyloid plaques) on the one hand, and specific tissue changes (atrophy) that are associated with AD on the other hand. This section includes three papers on qualitative and three on quantitative structural MRI methods. Imaging of amyloid plaques is one of the current challenges of MRI in the field of Alzheimer's disease. In qualitative structural MRI sub-section, Ryan Chamberlain and co workers focus on advances made in visualization of amyloid beta (Aβ) plaques with magnetic resonance imaging using different lines of transgenic mouse models of AD with emphasis on the recent longitudinal studies that enabled the visualization of plaque development in the same animals with age and their future impact on drug discovery. In addition, potential applications and challenges in the translation of these methods for visualizing plaques in humans are discussed. Alexandra Petiet and Marc Dhenain present an overview of plaque visualization using MR contrast agent. They also discuss the current issues related to amyloid specific and non-specific contrast agents such as their concentrations and difficulties to pass through the blood brain barrier. In addition to plaque visualization, the axonal function can be evaluated by structural MRI tools. Zaim Wadghiri and Anne Bertrand discuss the use of manganese enhanced MRI for in vivo evaluation of axonal function in transgenic mouse model of AD. Kejal Kantarci and colleagues discuss the application of diffusion tensor imaging as a sensitive, quantitative, tool to get access to the tissue microstructures, such as the disruption of myelin and axons in the white matter and neuronal cell bodies in the grey matter during the progression of AD. The quantitative measurements of regional atrophy in MR images and its application to AD diagnosis are reviewed by Faiza Admiraal-Behloul and co-workers. The prospective of mathematical modeling and feature extraction in MR images for probing crucial quantitative changes associated with AD is discussed by Michael Muskulus and Sjoerd Verduyn Lunel. VASCULAR MRI Vascular abnormalities are commonly observed in association with the parenchymal changes in AD. Nicolau Beckmann discusses the use of MRI to detect cerebrovascular alterations in both mouse models and in human patients. Application of cerebral blood volume measurements, arterial spins labeling for perfusion assessment, and MR angiography for probing vascular architecture are addressed. Arterial spins labeling (ASL) provides a non-invasive measurement of cerebral blood flow at a very high resolution by magnetically labeling the blood in the main brain-feeding arteries and subsequently detecting the labeled spins in the cerebral tissue after a delay. The use of arterial spin labeling perfusion MRI in AD is discussed in detail by Matthias van Osch and Hanzhang Lu. The added value of ASL perfusion studies and its future prospective for distinguishing between AD and other forms of dementia is critically reviewed by Norbert Schuff. MR SPECTROSCOPY Magnetic resonance spectroscopy (MRS) is a powerful tool for non invasive monitoring of the disease progression at a molecular level. Longitudinal and non-longitudinal single voxel MRS studies in AD patients and transgenic mouse models are summarised by Firat Kara and co-workers. The potential use of MRS for therapeutic studies in AD mice is also discussed. Furthermore, the future prospective in using 2D MRS for unearthing new biomarkers of AD is addressed. Chemical shift imaging has the ability to simultaneously measure metabolite concentrations in multiple areas of the brain. Although CSI has been available for nearly a decade, it has not been widely used for AD research. Christopher Scott and co-workers present an introduction to chemical shift imaging and examined the current state of chemical shift imaging in the investigation of AD and highlights the technological advances that will drive future developments and its applications to AD. CONCLUDING COMMENTS The organization of this special issue on “Prospects of Magnetic Resonance Imaging for Alzheimer's Disease” began with the idea of making a special effort to compile the scattered information into a full comprehensive journal issue on the application of MRI to AD. In this special issue a number of experts have written papers reviewing the application of MRI to AD and further discuss the future prospects of using MRI for improved diagnosis and prediction of AD. Every paper underwent a standard peer review by two independent referees, in addition to review by one of the Guest Editors or the Editor-in-Chief. We hope that the article in this special issue can form a useful reference and will help to stimulate and disseminate further research and clinical applications of MRI for diagnosis and understanding the AD and its widespread adoption into clinical practice.

A major objective in the treatment of Alzheimer's disease is amyloid plaque reduction. Transgenic mouse models of Alzheimer's disease provide a controlled and consistent environment for studying amyloid plaque deposition in Alzheimer's disease. Magnetic resonance imaging is an attractive tool for longitudinal studies because it offers noninvasive monitoring of amyloid plaques. Recent studies have demonstrated the ability of magnetic resonance imaging to detect individual plaques in living mice. This review discusses the mouse models, MR pulse sequences, and parameters that have been used to image plaques and how they can be optimized for future studies.

Overaccumulation of β-amyloid in the brain is believed to be a primary event in the development of Alzheimer's disease (AD). This amyloid is the target of drugs currently under development for the treatment of AD, which makes imaging amyloid plaques essential. Magnetic resonance imaging (MRI) has the resolution required to resolve these microscopic lesions (∼ 50 μm). In the absence of any contrast agent, the source of MR contrast in the amyloid plaques comes from the accumulation of iron, which shows as hypointense spots in T2, T2* or susceptibility-weighted images. Iron deposition in the brain is an age-related phenomenon and its accumulation occurs mainly in iron-rich regions. For plaques weakly loaded with iron, whose detection is much more challenging, the use of exogenous contrast agents (CA) becomes necessary. This article describes (1) targeted CAs made of a paramagnetic element like Gadolinium linked to a pharmacophore that targets amyloid, and (2) non-targeted CAs, an alternative to enhance amyloid plaque visualization. A background on CAs is also presented, and current issues related to contrast-enhanced MR imaging, including difficulties in delivering these agents across the blood-brain barrier, are also discussed.

Axonal transport perturbations are known to play a critical role in the pathological progression of Alzheimer's disease (AD); and Manganese-Enhanced MRI (MEMRI) provides a unique, non-invasive tool allowing for the in vivo evaluation of transport deficits in preclinical studies. In this paper, we provide a brief history of MEMRI, and review the current literature describing its biological basis. We propose a model of how manganese transport reflects both axonal and dendritic transport (termed “neuronal transport”), and potentially, mitochondrial trafficking in neurons. A framework for the analysis of MEMRI data is provided. It summarizes the significance of the various parameters describing manganese transport and the pathophysiological events that can alter their relevance, such as neuronal loss, gliosis and excitotoxicity. Lastly, we review publications describing different animal models of AD pathology that suggest the expression of either mutated human tau or mutated human amyloid β alters neuronal transport, as measured by MEMRI. In this way, MEMRI correlates the in vitro observation of impaired axonal transport and mitochondrial mislocalization related to AD lesions, with direct in vivo data. Therefore, MEMRI has the potential to become a unique tool for assessing the effect of new AD treatments aimed at restoring neuronal transport and mitochondrial trafficking.

Diffusion tensor imaging (DTI) provides information on tissue microstructure that is different from conventional T1 and T2-weighted MRI. Although, the value of DTI is likely to be greatest for assessing white matter degeneration in Alzheimer's disease (AD), cross-sectional DTI studies consistently show increased diffusivity in gray matter regions that are typically involved with the neurodegenerative pathology in AD such as the medial temporal lobes and temporoparietal association cortices. The white matter tracts that connect these gray matter regions such as the limbic pathways, long association fibers of inferior and superior longitudinal fasciculi also show elevated diffusivity and decreased directionality of diffusivity. Although the pathological underpinnings of DTI abnormalities in AD are yet unclear, DTI changes in AD are thought to represent disruption of myelin and axons in the white matter and neuronal cell bodies in the gray matter.

Alzheimer's disease (AD) is a progressive disease usually accompanied by regional atrophy that can be detected noninvasively using structural magnetic resonance imaging (MRI). An abundant literature has demonstrated the value of quantitative measurements of regional atrophy in AD, suggesting that MR based volumetry and morphometry could be valuable and useful in clinical practice. The aim of this paper is mainly to recall the most critical points to consider when using MRI for automated brain volumetry and morphometry and review briefly the main findings in the literature on brain volumetry and morphometry in AD.

Transverse relaxation time T2 and magnetization transfer ratio MTR are examples of two magnetic resonance imaging parameters that allow for a sensitive characterization of microscopic tissue properties in the brain. Classically, the mean values of these parameters are assessed in a region-of-interest and compared groupwise. In contrast to this, modern voxel-based methods test for localized changes in imaging parameters on a per-voxel basis, by registering the image to an average brain template or atlas. An intermediary method is distributional analysis, where the distribution of an imaging parameter over an anatomical region, identified from a brain atlas, is the main object of interest. This distribution captures local variation and changes in tissue properties and can ideally be described by a parametric mixture model. It can directly be compared across subjects by a distance measure and classification of subjects can be based on features extracted from these distributions of imaging parameters. This approach reduces the high dimensionality of the data and, consequently, the impact of noise and avoids the problem of collinearity. In this article the applicability of these and related methods of feature extraction and discrimination is reviewed in the context of Alzheimer's disease.

Vascular abnormalities commonly coexist with the histological features of Alzheimer's disease (AD). Deposition of amyloid-β peptide in cerebral vessel walls, known as cerebral amyloid angiopathy, is very frequent, but it is unclear whether CAA is triggering AD or is contributing to later phases in pathology. In this paper, the use of MRI to detect cerebrovascular changes in murine models of AD and in patients is addressed. As reduced blood flow is a consistent physiological deficit reported in individuals suffering from AD, perfusion MRI has a particular relevance. Moreover, because of their sensitivity to turbulences, angiographic or phase-contrast techniques have the potential to detect small alterations of vessels translating into minor flow disturbances. Cerebral blood volume assessments allow to study functional deficits before gross morphological alterations of associated brain regions. Despite initial encouraging results, the discussed techniques still need to be properly validated, either diagnostically or as a tool for drug discovery. The further characterization in murine models along tests in large-scale, epidemiologically rigorous, human studies are going to contribute to establish the true utility of MRI as a tool to visualize AD-related cerebrovascular alterations in experimental animals and in patients.

Although nuclear medicine imaging methods such as Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) were the first to show a distinctive pattern of hypometabolism and hypoperfusion in patients with Alzheimer's disease (AD), large-scale application of these methods is hampered by invasiveness, high costs, low spatial resolution and availability. Recent findings that hemodynamic changes precede cortical thinning have resulted in a strong interest in developing a non-invasive alternative for measuring the hemodynamic status. Magnetic resonance imaging (MRI) provides a non-invasive measurement of cerebral blood flow by magnetically labeling the blood in the main brain-feeding arteries and subsequently detecting the labeled spins in the cerebral tissue after a delay. This technique has been dubbed “Arterial spin labeling (ASL)”. Image quality of ASL has been considerably improved in recent years, owing to the development of medium and high field MRI scanners, improved methods to suppress physiological noise, and improved labeling sequences. In this review article the technique of ASL MRI is introduced and an overview of studies that employ ASL in AD is provided. A common finding over these studies is that CBF is reduced in bilateral precunei, parietal and temporal lobes, frontal areas, and occipital areas. These findings are in line with PET and SPECT findings, but ASL studies have also shown new results that were not previously observed in nuclear medicine studies. The most interesting finding is probably the observed increase in CBF (after atrophy correction) in the hippocampus.

The development of an accurate marker for Alzheimer's disease (AD) at the earliest stage is an important public health goal. Modern neuroimaging techniques offer one potential approach to identify a marker for AD. This review focuses on the detection of alterations in brain perfusion as a potentially sensitive index of AD pathology using arterial spin labeling (ASL) perfusion mapping - a relatively new variant of magnetic resonance imaging (MRI). Key findings of ASL perfusion studies in AD mild cognitive impairment (MCI), a transitional stage between normal aging and AD as well as in other forms of dementia are discussed. Furthermore, the value of ASL-MRI for improved diagnosis and prediction of AD is critically reviewed.

In vivo magnetic resonance spectroscopy is a powerful tool which can be applied non-invasively to monitor disease progression at a molecular level in the brain of human patients with Alzheimer's disease (AD) and transgenic mouse models of AD. Application of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in transgenic mouse models of AD makes it possible to follow metabolic changes and structural changes at the same time longitudinally. This review focuses on in vivo MRS studies in transgenic mouse models of AD and highlights the future impact of MRS techniques in finding crucial biomarkers of AD.

With the global prevalence of Alzheimer's Disease expected to double in the next twenty years, the importance of early diagnosis and biomarkers for disease progression has never been more important. Magnetic Resonance Spectroscopy (MRS) is becoming an increasingly important tool for measuring pathology, disease progression, and drug treatment effects. 2D and 3D Chemical Shift Imaging (CSI) is a burgeoning technique that may play an even more key role as technology advances, allowing for faster and more accurate acquisition while acquiring more myriad data than conventional single-voxel MRS. Measurement of brain metabolites in vivo, such as N-acetyl-aspartate, choline, creatine, myoinositol, glutamate, and glutamine, allows researchers and clinicians alike to better understand the complex processes and interactions that are occurring in the brain from normal ageing, through mild cognitive impairment to dementia and Alzheimer's Disease. This review examines the current state of 2D/3D CSI research on Alzheimer's Disease, including a brief history of spectroscopy, current applications, biological and technical challenges, and highlights of technological advances that will drive future development of the technique.