Noninvasive in vivo MRI detection of neuritic plaques associated with iron in APP[V717I] transgenic mice, a model for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by a progressive decline of cognitive function, while the neuropathologic features include the occurrence of neurofibrillary tangles, neuritic plaques, decreased synaptic density, and loss of neurons. Neuritic plaques consist of extracellular ␤-amyloid (A␤) deposits surrounded by dystrophic neuritis (1). The plaques are neurotoxic and induce inflammatory responses. According to the amyloid cascade hypothesis, the increased amyloid deposition results in the onset and progression of AD (2,3,4,5) and therefore amyloid plaques became crucial as a target for many therapeutic approaches (6,7).Despite the impact of in vivo imaging techniques in daily clinical practice and also in neuroscience, typical Alzheimer plaques were never visualized in vivo in patients. To diagnose AD and to differentiate from other dementias, the detection of at least one typical hallmark, i.e., amyloid plaques or neurofibrillary tangles, appears essential. To date, accumulations of amyloid in AD patients have been observed only postmortem. Recently, however, significant progress has been made visualizing AD plaques using transgenic mouse models for AD. Skovronsky et al. (8) reported in vivo labeling of amyloid plaques in transgenic mice using a radiolabeled ligand but detection was still performed postmortem with fluorescence microscopy. Another attempt to demonstrate plaques postmortem used MRI and was based on injection of a specific derivative of the amyloid peptide with a high molecular specificity for amyloid as a label, i.e., putrescine-gadolinium-A␤ (9). Finally, Wadghiri et al. (10) used systemic injection of monocrystalline iron oxide nanoparticles or gadolinium (Gd) labeled A␤ 1-40 peptide with a high affinity for A␤ and were able to detect ex vivo but also in vivo amyloid plaques in the affected mouse brains. In this approach, the main obstacle for amyloid labeling remains the blood brain barrier and its transient opening using mannitol must be considered quite invasive. Another drawback may be the authentication of amyloid plaques and the exclusion of the involvement of blood vessels embedded with contrast agent, which requires subsequent histology of the brain.The first MRI study that demonstrated amyloid plaques without any exogenous labeling was performed by Benveniste et al. in 1999 (11). Three dimensional T 2 * images of postmortem human AD brain samples, acquired in more than 2.7 hr, revealed dark spots in the brain correlating with histologic amyloid staining. Recently, using T 2 MR contrast, identification of plaque-like structures in the cortex and hippocampus of fixed mouse brain was reported by Zhang et al. (12). However, the authors did not explain the source of the MR contrast in relation to the physiologic processes related with plaque formation and the evidence was only confirmed by the subsequent co registration of plaques by histology. Analogous to this finding, Helpern et al. (13) demonstrated a reduced T 2 value in the cortex and hippocampus in vivo in an AD mouse model,...

Cortical phase changes in Alzheimer's disease at 7T MRI: A novel imaging marker

“…Similar patterns have been described in studies of AD transgenic mice and postmortem human AD cases, and were attributed to the presence of amyloid plaques using histological confirmation [11][12][13][14][15][16][17][18][19]. It has been proposed that the visualization on MRI of plaques in humans and mice is based on the fact that these deposits colocalize with iron, which gives rise to magnetic susceptibility effects on T2*-weighted images over volumes that are much larger than the actual size of amyloid plaques [17,[19][20][21][22][23][24]. An alternative method to measure these susceptibility changes in the brain is to measure the relative phase in regions of interest (ROIs), because it has been shown that this is a reliable indicator of the iron content in the brain [25][26][27][28].…”

“…These features included hypointense foci and diffuse granular patterns of less distinct hypointense foci in the cerebral cortex [10]. Similar patterns have been described in studies of AD transgenic mice and postmortem human AD cases, and were attributed to the presence of amyloid plaques using histological confirmation [11][12][13][14][15][16][17][18][19]. It has been proposed that the visualization on MRI of plaques in humans and mice is based on the fact that these deposits colocalize with iron, which gives rise to magnetic susceptibility effects on T2*-weighted images over volumes that are much larger than the actual size of amyloid plaques [17,[19][20][21][22][23][24].…”

A non-toxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice

“…Similar to previous ex vivo- (Lee et al, 2004;Zhang et al, 2004) and in vivo reports (Jack et al, 2004(Jack et al, , 2005Sigurdsson et al, 2004b;Vanhoutte et al, 2005), we were able to image some amyloid lesions in our AD transgenic mice without the use of a contrast agent. With our relatively short imaging times, only a small proportion of amyloid lesions could be detected without the use of a contrast agent.…”

“…With our relatively short imaging times, only a small proportion of amyloid lesions could be detected without the use of a contrast agent. This direct detection of amyloid lesions most likely reflects iron content within plaques (Falangola et al, 2005;Jack et al, 2004Jack et al, , 2005Vanhoutte et al, 2005;. Iron deposition has been previously reported both in AD and in transgenic AD mouse model plaques, in particular in more mature lesions (Smith et al, 1997(Smith et al, , 1998.…”

Selective Contrast Enhancement of Individual Alzheimer’s Disease Amyloid Plaques Using a Polyamine and Gd-DOTA Conjugated Antibody Fragment Against Fibrillar Aβ42 for Magnetic Resonance Molecular Imaging

“…In the study by Poduslo et al (6), whole AD mice brains were imaged ex vivo and individual amyloid plaques were identified after intravenous administration of an exogenous plaque labeling contrast agent. Another approach is to image individual amyloid plaques without any contrast agent utilizing the endogenous iron content present in the amyloid plaques (5,6,(8)(9)(10)(11).…”