Passive staining: a novel ex vivo MRI protocol to detect amyloid deposits in mouse models of Alzheimer's disease.

Amyloid plaques are one of the hallmarks of Alzheimer's disease (AD). This study evaluated a novel microMRI strategy based on "passive staining" of brain samples by gadoteric acid. The protocol was tested at 4.7 T on control animals and APP/PS1 mice modeling AD lesions. T(1) was strongly decreased in passively stained brains. On high-resolution 3D gradient echo images, the contrast between the cortex and subcortical structures was highly improved due to a T2* effect. The brains of APP/PS1 mice revealed plaques as hypo-intense spots. They appeared larger in long compared to short TE images. This suggests that, after passive staining, plaques caused a susceptibility effect. This easily performed protocol is a complementary method to classic histology to detect the 3D location of plaques. It may also be used for the validation of in vivo MRI protocols for plaque detection by facilitating registration with histology via post mortem MRI.     

MRI assessment of neuropathology in a transgenic mouse model of Alzheimer's disease.

The cerebral deposition of amyloid beta-peptide, a central event in Alzheimer's disease (AD) pathogenesis, begins several years before the onset of clinical symptoms. Noninvasive detection of AD pathology at this initial stage would facilitate intervention and enhance treatment success. In this study, high-field MRI was used to detect changes in regional brain MR relaxation times in three types of mice: 1). transgenic mice (PS/APP) carrying both mutant genes for amyloid precursor protein (APP) and presenilin (PS), which have high levels and clear accumulation of beta-amyloid in several brain regions, starting from 10 weeks of age; 2). transgenic mice (PS) carrying only a mutant gene for presenilin (PS), which show subtly elevated levels of Abeta-peptide without beta-amyloid deposition; and 3). nontransgenic (NTg) littermates as controls. The transverse relaxation time T(2), an intrinsic MR parameter thought to reflect impaired cell physiology, was significantly reduced in the hippocampus, cingulate, and retrosplenial cortex, but not the corpus callosum, of PS-APP mice compared to NTg. No differences in T(1) values or proton density were detected between any groups of mice. These results indicate that T(2) may be a sensitive marker of abnormalities in this transgenic mouse model of AD.     

Detection of Alzheimer's amyloid in transgenic mice using magnetic resonance microimaging.

The presence of amyloid-beta (Abeta) plaques in the brain is a hallmark pathological feature of Alzheimer's disease (AD). Transgenic mice overexpressing mutant amyloid precursor protein (APP), or both mutant APP and presenilin-1 (APP/PS1), develop Abeta plaques similar to those in AD patients, and have been proposed as animal models in which to test experimental therapeutic approaches for the clearance of Abeta. However, at present there is no in vivo whole-brain imaging method to detect Abeta plaques in mice or men. A novel method is presented to detect Abeta plaques in the brains of transgenic mice by magnetic resonance microimaging (muMRI). This method uses Abeta1-40 peptide, known for its high binding affinity to Abeta, magnetically labeled with either gadolinium (Gd) or monocrystalline iron oxide nanoparticles (MION). Intraarterial injection of magnetically labeled Abeta1-40, with mannitol to transiently open the blood-brain barrier (BBB), enabled the detection of many Abeta plaques. Furthermore, the numerical density of Abeta plaques detected by muMRI and by immunohistochemistry showed excellent correlation. This approach provides an in vivo method to detect Abeta in AD transgenic mice, and suggests that diagnostic MRI methods to detect Abeta in AD patients may ultimately be feasible.     

In vivo measurement of plaque burden in a mouse model of Alzheimer's disease

PURPOSE: To demonstrate an MRI method for directly visualizing amyloid-beta (Abeta) plaques in the APP/PS1 transgenic (tg) mouse brain in vivo, and show that T1rho relaxation rate increases progressively with Alzheimer's disease (AD)-related pathology in the tg mouse brain. MATERIALS AND METHODS: We obtained in vivo MR images of a mouse model of AD (APP/PS1) that overexpresses human amyloid precursor protein, and measured T1rho via quantitative relaxometric maps. RESULTS: A significant decrease in T1rho was observed in the cortex and hippocampus of 12- and 18-month-old animals compared to their age-matched controls. There was also a correlation between changes in T1rho and the age of the animals. CONCLUSION: T1rho relaxometry may be a sensitive method for noninvasively determining AD-related pathology in APP/PS1 mice.     

MRI and histological analysis of beta‐amyloid plaques in both human Alzheimer's disease and APP/PS1 transgenic mice

Purpose

To investigate the relationship between MR image contrast associated with beta‐amyloid (Aβ) plaques and their histology and compare the histopathological basis of image contrast and the relaxation mechanism associated with Aβ plaques in human Alzheimer's disease (AD) and transgenic APP/PS1 mouse tissues.

Materials and Methods

With the aid of the previously developed histological coil, T‐weighted images and R parametric maps were directly compared with histology stains acquired from the same set of Alzheimer's and APP/PS1 tissue slices.

Results

The electron microscopy and histology images revealed significant differences in plaque morphology and associated iron concentration between AD and transgenic APP/PS1 mice tissue samples. For AD tissues, T contrast of Aβ‐plaques was directly associated with the gradation of iron concentration. Plaques with significantly less iron load in the APP/PS1 animal tissues are equally conspicuous as the human plaques in the MR images.

Conclusion

These data suggest a duality in the relaxation mechanism where both high focal iron concentration and highly compact fibrillar beta‐amyloid masses cause rapid proton transverse magnetization decay. For human tissues, the former mechanism is likely the dominant source of R relaxation; for APP/PS1 animals, the latter is likely the major cause of increased transverse proton relaxation rate in Aβ plaques. The data presented are essential for understanding the histopathological underpinning of MRI measurement associated with Aβ plaques in humans and animals. J. Magn. Reson. Imaging 2009;29:997–1007. © 2009 Wiley‐Liss, Inc.     

阿尔茨海默病的放射性分子显像探针研究进展

阿尔茨海默病(AD)是引起痴呆的最常见类型之一,其主要病理改变包括由β-淀粉样蛋白构成的老年斑、神经原纤维缠结。在体观察AD脑内的β-淀粉样蛋白沉积,可为AD的诊断、疗效观察和治疗药物的研究提供很大帮助。目前已合成数种标记β-淀粉样蛋白的放射性探针并开始用于PET对AD患者脑内老年斑的在体显像研究,并显示出潜在的临床应用价值。AD的放射性分子显像探针仍需进一步研究,使其不仅适用于PET,而且还可以满足SPECT的显像要求。     

Transverse relaxation time reflects brain amyloidosis in young APP/PS1 transgenic mice.

Amyloid deposits are one of the hallmarks of Alzheimer's disease (AD), one of the most devastating neurodegenerative disorders. In transgenic mice modeling Alzheimer's pathology, the MR transverse relaxation time (T(2)) has been described to be modulated by amyloidosis. This modification has been attributed to the age-related iron deposition that occurs within the amyloid plaques of old animals. In the present study, young APP/PS1 transgenic mice without histochemically detectable iron in the brain were specifically studied. In vivo measurements of T(2) in the hippocampus, at the level of the subiculum, were shown to reflect the density of amyloid plaques. This suggests that T(2) variations can be induced solely by aggregated amyloid deposits in the absence of associated histologically-detectable iron. Thus T(2) from regions with high amyloid load, such as the subiculum, is particularly well suited for following plaque deposition in young animals, i.e., at the earliest stages of the pathological process.     

Biphenyls labeled with technetium 99m for imaging beta-amyloid plaques in the brain

Formation and accumulation of excess aggregates of beta-amyloid (Abeta) plaques in the brain are critical factors contributing to the development and progression of Alzheimer's disease (AD). There is an urgent need for in vivo imaging agents that can specifically demonstrate the location and density of Abeta plaques in the brain. The aim of this study was to develop potential technetium 99m (99mTc)-labeled diagnostic imaging agents specific for the detection of Abeta plaques. Based on previously obtained Abeta plaque-specific biphenyls containing a p-N, N-dimethylaminophenyl group, a series of 99mTc and Re-N2S2-biphenyl derivatives was prepared. The stable neutral and lipophilic 99mTc complexes, [99mTc]19 and [99mTc]23, A+B, were successfully obtained. As surrogates for the 99mTc complexes, the corresponding surrogates, Re complexes of 23, were also prepared. Surprisingly, it was found that the Re complexes showed distinctively different retention profiles as compared with the corresponding 99mTc complexes. Biodistribution studies indicated that [99mTc]23A readily passed through the blood-brain barrier (1.18% dose/brain at 2 min) in contrast to the low brain penetration of [99mTc]19 (0.29% dose/brain at 2 min). Initial results suggested that [99mTc]23A showed selective binding to the Abeta plaque-like structures in the brain sections from transgenic mice but not in the postmortem human brain tissue of patients with confirmed AD. The results provide encouraging evidence that development of a 99mTc-labeled agent for imaging Abeta plaques in the brain may be feasible. Caution should be taken when comparing these 99mTc complexes with the corresponding surrogates--the Re complexes.     

11C-labeled stilbene derivatives as Abeta-aggregate-specific PET imaging agents for Alzheimer's disease

A series of stilbene derivatives as potential diagnostic imaging agents targeting amyloid plaques in Alzheimer's disease (AD) were synthesized and evaluated. The syntheses of the stilbenes were successfully achieved by a simple Wadsworth-Emmons reaction between diethyl (4-nitrobenzyl)phosphonate and 4-methoxybenzaldehyde. 4-N,N-dimethylamino-4'-methyoxy and the corresponding 4-N-monomethylamino-, 4'-hydroxy stilbenes showed good binding affinities towards Abeta aggregates in vitro (K(i) < 10 nM). The (11)C labeled 4-N-methylamino-4'-hydroxystilbene, [(11)C]4, was prepared by (11)C methylation of 4-amino-4'-hydroxystilbene. The [(11)C]4 displayed a moderate lipophilicity (log P = 2.36), and showed a very good brain penetration and washout from normal rat brain after an iv injection. In vitro autoradiography of transgenic AD mouse brain sections showed a high specific labeling of beta-amyloid plaques, whereas the control sections showed no binding. Taken together the data suggest that a relatively simple stilbene derivative, [(11)C]4, N-[(11)C]methylamino-4'-hydroxystilbene, may be useful as a positron emission tomography (PET) imaging agent for mapping Abeta plaques in the brain of patients with Alzheimer's disease.     

Gradient-echo and CRAZED imaging for minute detection of Alzheimer plaques in an APPV717I x ADAM10-dn mouse model.

Different strategies to visualize amyloid plaques with MRI at 17.6 Tesla were investigated in a novel mouse model of Alzheimer's disease (AD). Large iron-containing plaques were observed in the thalamus, but cortical plaques did not show iron deposits. Plaques in the thalamus were visualized in vivo with the use of low-resolution, 3D gradient-echo (GRE) imaging in 82 s, and with 94-microm resolution in 34 min. The feasibility of obtaining bright contrast from plaques using the COSY revamped with asymmetric z-GRE detection (CRAZED) technique was investigated in experiments on fixed brains. The original CRAZED approach provided reduced signal near the plaques (similarly to GRE imaging) and additionally emphasized small structures in the brain. In CRAZED images acquired with mismatched gradients, elevated signal near the plaques was obtained, while background signal was suppressed almost to the noise level. Bright-contrast images were acquired in 2.6 min with the use of a 2D GRE sequence with slightly mismatched slice refocusing gradients. For future detection of plaques in patients, such bright-contrast visualization protocols may be of particular value when contrast agents that allow labeling of early plaques with iron oxide nanoparticles become available.     

Synthesis and biological evaluation of (E)-3-styrylpyridine derivatives as amyloid imaging agents for Alzheimer's disease

A new series of (E)-3-styrylpyridine derivatives as potential diagnostic imaging agents targeting amyloid plaques in Alzheimer's disease (AD) were synthesized and examined. When in vitro binding studies using AD brain homogenates were carried out with a series of styrylpyridine derivatives, (E)-2-Bromo-5-(4-dimethylaminostyryl)pyridine (7) with a dimethylamino group showed the highest binding affinity. Compound 7 intensely stained neuritic and diffused plaques and cerebrovascular amyloids on postmortem AD brain sections. (E)-2-Iodo-5-(4-dimethylaminostyryl)pyridine, the iodo derivative of compound 7, also stained senile plaques in human AD sections. The radioiodinated ligand [125I] was successfully prepared through an iododestannylation reaction from the corresponding tributyltin derivatives using hydrogen peroxide as the oxidant in high yields and with high radiochemical purity. A biodistribution study in normal mice after an intravenous injection of [125I] displayed high brain uptake and fast washout. Taken together, the data suggest that the new radio tracer, [125I], may be useful as a radioiodinated imaging agent for mapping A beta plaques in the brains of patients with AD.     

Fluorine-18 labeling of three novel D-peptides by conjugation with N-succinimidyl-4-[18F]fluorobenzoate and preliminary examination by postmortem whole-hemisphere human brain autoradiography

Introductionβ-Amyloid (Aβ) plaques and neurofibrillary tangles are the main characteristics of Alzheimer's disease (AD). Positron emission tomography (PET), a high-resolution, sensitive, and noninvasive imaging technique, has been widely utilized in visualizing the localization of plaques and tangles and thereby distinguishing between AD and healthy controls. A small 12-mer d-enantiomeric peptide (amino acid sequence=QSHYRHISPAQV), denoted as D1, has high binding affinity to Aβ in vitro in the sub-micromolar range, and consequently, its radiolabeled analogues have a potential as radioligands for visualizing amyloid plaques in vivo by PET.AimThe aims of the present work were to develop three different potent D1 derivative peptides labeled with fluorine-18 and to examine them in the AD and control postmortem human brain by autoradiography (ARG).MethodsThree different D1 derivative peptides were radiolabeled with fluorine-18 ([¹⁸F]ACI-87, [¹⁸F]ACI-88, [¹⁸F]ACI-89) using the prosthetic group N-succinimidyl-4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB) and purified by high performance liquid chromatography (HPLC). Preliminary ARG measurements were performed in AD and control brains.ResultsThe three fluorine-18-labeled d-peptides were obtained in a total synthesis time of 140 min with radiochemical purity higher than 98%. The specific radioactivities of the three different D1 derivative peptides were between 9 and 113 GBq/μmol. ARG demonstrated a higher radioligand uptake in the cortical gray matter and the hippocampus in the AD brain as compared to age-matched control brain.ConclusionsFluorine-18 labeling of the three novel D1 derivative peptides using [¹⁸F]SFB was successfully accomplished. Higher contrast between AD and control brain slices demonstrates their potential applicability for further use in vivo by PET.     

18F-labeled styrylpyridines as PET agents for amyloid plaque imaging

Positron emission tomography (PET) imaging of beta-amyloid (Abeta) plaques in the brain is a potentially valuable tool for studying the pathophysiology of Alzheimer's disease (AD). It may also be applicable for measuring the effectiveness of therapeutic drugs aimed at lowering Abeta plaques in the brain. We have successfully reported a series of 18F-labeled fluoropegylated stilbenes for PET imaging studies. Encouraging results clearly demonstrated the usefulness of 18F-labeled stilbenes as potential Abeta plaque-imaging agents. In the present study, we applied a similar approach to a styrylpyridine backbone structure. Among all derivatives examined, (E)-2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-5-(4-dimethylaminostyryl)-pyridine (2) displayed high binding affinity in postmortem AD brain homogenates (Ki=2.5+/-0.4 nM, with [125I]IMPY as radioligand). No-carrier-added [18F]2 was successfully prepared by [18F]fluoride displacement of the corresponding tosylate precursor with a high labeling yield (30-40%) and a high radiochemical purity (>99%). Specific activity at the end of synthesis was determined to be 1500-2000 Ci/mmol. The tracer [18F]2 showed adequate lipophilicity (log P=3.22). In vivo biodistribution of [18F]2 in normal mice exhibited excellent initial brain penetration and rapid washout (7.77% and 1.03% dose/g in the brain at 2 and 30 min after intravenous injection, respectively)--properties that are highly desirable for Abeta-plaque-specific brain imaging agents. Autoradiography of AD brain sections and homogenate binding with postmortem AD brain tissues confirmed the high binding signal of [18F]2 due to the presence of Abeta plaques. These preliminary results suggest that novel PET tracers may be potentially useful for the imaging of Abeta plaques in the living human brain.     

Automatic segmentation of amyloid plaques in MR images using unsupervised support vector machines

Deposition of the β-amyloid peptide (Aβ) is an important pathological hallmark of Alzheimer's disease (AD). However, reliable quantification of amyloid plaques in both human and animal brains remains a challenge. We present here a novel automatic plaque segmentation algorithm based on the intrinsic MR signal characteristics of plaques. This algorithm identifies plaque candidates in MR data by using watershed transform, which extracts regions with low intensities completely surrounded by higher intensity neighbors. These candidates are classified as plaque or nonplaque by an unsupervised learning method using features derived from the MR data intensity. The algorithm performance is validated by comparison with histology. We also demonstrate the algorithm's ability to detect age-related changes in plaque load ex vivo in amyloid precursor protein (APP) transgenic mice that coexpress five familial AD mutations (5xFAD mice). To our knowledge, this study represents the first quantitative method for characterizing amyloid plaques in MRI data. The proposed method can be used to describe the spatiotemporal progression of amyloid deposition, which is necessary for understanding the evolution of plaque pathology in mouse models of Alzheimer's disease and to evaluate the efficacy of emergent amyloid-targeting therapies in preclinical trials.     

Dimethylamino-fluorenes: ligands for detecting beta-amyloid plaques in the brain

Formation of beta-amyloid (Abeta) plaques in the brain is a major contributing factor in the pathogenesis of Alzheimer's disease (AD). Detection of Abeta plaques in the brain will be potentially useful in early diagnosis and monitoring the progression of the disease. A series of novel Abeta aggregate-specific ligands based on fluorenes, which are simple and rigid tricyclic molecules, are synthesized and characterized. Starting with 2- or 3-aminofluorenes, 1a-1f, the amino group was converted to the N,N-dimethylamino group (2a-2f) in excellent yield. It was found that 7-iodo-2-N,N-dimethylaminofluorene (2f) showed an extremely high binding affinity to preformed Abeta40 aggregates (K(i) = 0.9 nM). In vitro autoradiography study using brain sections obtained from transgenic mice (Tg2576) with [(125)I]2f showed exquisitely high specific binding to Abeta plaques. The same section also displayed an equivalent labeling when stained by Thioflavin-S, a commonly used fluorescent dye for Abeta plaques. When [(125)I]2f was injected intravenously into normal mice, it exhibited an excellent brain uptake. Taken together the data suggest that [(125)I]2f may be useful as an in vivo imaging agent to detect Abeta plaques in the brain.     

In vivo quantitative whole-brain diffusion tensor imaging analysis of APP/PS1 transgenic mice using voxel-based and atlas-based methods

Introduction

Diffusion tensor imaging (DTI) has been applied to characterize the pathological features of Alzheimer's disease (AD) in a mouse model, although little is known about whether these features are structure specific. Voxel-based analysis (VBA) and atlas-based analysis (ABA) are good complementary tools for whole-brain DTI analysis. The purpose of this study was to identify the spatial localization of disease-related pathology in an AD mouse model.

Methods

VBA and ABA quantification were used for the whole-brain DTI analysis of nine APP/PS1 mice and wild-type (WT) controls. Multiple scalar measurements, including fractional anisotropy (FA), trace, axial diffusivity (DA), and radial diffusivity (DR), were investigated to capture the various types of pathology. The accuracy of the image transformation applied for VBA and ABA was evaluated by comparing manual and atlas-based structure delineation using kappa statistics. Following the MR examination, the brains of the animals were analyzed for microscopy.

Results

Extensive anatomical alterations were identified in APP/PS1 mice, in both the gray matter areas (neocortex, hippocampus, caudate putamen, thalamus, hypothalamus, claustrum, amygdala, and piriform cortex) and the white matter areas (corpus callosum/external capsule, cingulum, septum, internal capsule, fimbria, and optic tract), evidenced by an increase in FA or DA, or both, compared to WT mice (p?<?0.05, corrected). The average kappa value between manual and atlas-based structure delineation was approximately 0.8, and there was no significant difference between APP/PS1 and WT mice (p?>?0.05). The histopathological changes in the gray matter areas were confirmed by microscopy studies. DTI did, however, demonstrate significant changes in white matter areas, where the difference was not apparent by qualitative observation of a single-slice histological specimen.

Conclusion

This study demonstrated the structure-specific nature of pathological changes in APP/PS1 mouse, and also showed the feasibility of applying whole-brain analysis methods to the investigation of an AD mouse model.     

Demonstration of puromycin-sensitive alanyl aminopeptidase in Alzheimer disease brain

Puromycin-sensitive alanyl aminopeptidase (PSA, EC 3.4.11.14) is a member of the ubiquitous aminopeptidase family, which cleaves N-terminal amino acids from proteins. PSA is suggested to function as a trimming protease in the MHC class I pathway, which is activated in brains of Alzheimer disease (AD). We examined the immunohistochemical localization of PSA in brains of AD and control cases using a rabbit anti-PSA. In the control cases, the antiserum revealed staining in a few glial cells and blood vessels. In AD brain, however, intensely stained cells were found richly in the cerebral cortex. Double immunofluorescence studies confirmed that PSA-positive cells were reactive microglia. Such PSA-positive reactive microglia tended to locate in and around senile plaques and were sometimes observed to associate with neurons containing neurofibillary tangles. The present result indicates that reactive microglia express PSA-immunoreactive molecules, probably in association with the pathological conditions of AD.     

Validation of an 18F-labeled biphenylalkyne as a positron emission tomography imaging agent for β-amyloid plaques

AimRecently, the feasibility of detecting amyloid plaques in the living brain by positron emission tomography (PET) imaging has been successfully demonstrated. As such, imaging β-amyloid (Aβ) plaques in the brain may further advance the differential diagnosis of the disease and allow clinicians to measure the effectiveness of therapeutic drugs aimed at lowering plaques in the brain. We report herein the preclinical validation of a potential ¹⁸F-labeled biphenylalkyne, AV-138, as a preliminary step toward developing the imaging agent for patients suspected of having Alzheimer's disease.MethodsIn vitro binding was carried out in the homogenates prepared from postmortem AD brains with [¹²⁵I]IMPY as the radioligand. [¹⁸F]AV-138 was successfully prepared using a tosylate precursor and Sumitomo modules for radiosynthesis. Similarly, specific binding of [¹⁸F]AV-138 (0.02–0.05 nM) to homogenates, prepared from gray and white matters of pooled AD patients and control subjects, was performed. Specific binding to Aβ plaques was measured by autoradiography in AD brain sections (n=11), and the same brain sections were fluorescently stained with thioflavin-S (TF-S). Images of both radiolabeling and fluorescent staining of plaques obtained by a phosphor imager were used for correlation image analysis.ResultsAs expected, AV-138 displayed a high binding affinity (K_i=2.4±0.7 nM) in AD gray matter homogenates (due to its high level of Aβ plaque accumulation). Specific binding can be clearly measured in the AD gray matter homogenates, but not in the AD white matters. Control brain homogenates, due to a lack of Aβ plaques, also showed no specific binding. Furthermore, in vitro autoradiography of postmortem AD brain sections showed that the high binding signal of [¹⁸F]AV-138 was specifically due to Aβ plaques. Fluorescent staining of plaques with TF-S correlated well with the radiolabeling of [¹⁸F]AV-138 in AD brain sections (r>0.90).ConclusionTaken together, these preliminary results strongly suggest that [¹⁸F]AV-138 is potentially useful for imaging Aβ plaques in the living human brain.     

Benzofuran derivatives as Abeta-aggregate-specific imaging agents for Alzheimer's disease

The purpose of this study is to develop potential I-123 labeled diagnostic imaging agents targeting amyloid plaques in Alzheimer's disease (AD). Formation and accumulation of aggregates of beta-amyloid (Abeta) peptides in the brain are critical factors in the development and progression of AD. Small molecule-based benzofuran derivatives were designed and synthesized. Both 5- and 6-iodobenzofuran derivatives displayed excellent competition for I-125 TZDM binding to Abeta40 aggregates with K(i) values in the subnanomolar range. The radioiodinated ligands, with a high specific activity, were successfully prepared through an iododestannylation reaction from the corresponding tributyltin derivatives using hydrogen peroxide as the oxidant in high yields (60-80%) and with high radiochemical purities (greater than 95%). After an iv injection, all four radioiodinated ligands displayed high brain uptakes ranging from 0.5 to 1.5% initial dose/organ in normal mice. The radioactivity washed out from the mouse brain slowly (less than 50% at 2 h post injection), suggesting high in vivo non-specific binding. In conclusion, the benzofuran ligands displayed excellent binding affinity for Abeta aggregates. The long retention of these ligands in the normal mouse brain suggests that there may be high binding for these probes in the brain not associated with Abeta plaques. Additional modifications are necessary to improve the in vivo imaging properties for plaque detection.     

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

Transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP[V717I]) in neurons develop amyloid plaques in the brain, thus demonstrating the most prominent neuropathological hallmark of Alzheimer's disease. In vivo 3D T2*-weighted MRI on these mice (24 months of age) revealed hypointense brain inclusions that affected the thalamus almost exclusively. Upon correlating these MRI observations with a panel of different histologic staining techniques, it appeared that only plaques that were positive for both thioflavin-S and iron were visible on the MR images. Numerous thioflavin-S-positive plaques in the cortex that did not display iron staining remained invisible to MRI. The in vivo detection of amyloid plaques in this mouse model, using the intrinsic MRI contrast arising from the iron associated with the plaques, creates an unexpected opportunity for the noninvasive investigation of the longitudinal development of the plaques in the same animal. Thus, this work provides further research opportunities for analyzing younger APP[V717I] mouse models with the knowledge of the final outcome at 24 months of age.