Mark D. Meadowcroft

MRI and Histological Analysis of Beta-Amyloid Plaques in Both Human Alzheimer's Disease and APP/PS1 Transgenic Mice

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 Alzheimers disease (AD) and transgenic APP/PS1 mouse tissues.

Olfactory Deficit Detected by fMRI in Early Alzheimer’s Disease

Alzheimers disease (AD) is accompanied by smell dysfunction, as measured by psychophysical tests. Currently, it is unknown whether AD-related alterations in central olfactory system neural activity, as measured by functional magnetic resonance imaging (fMRI), are detectable beyond those observed in healthy elderly. Moreover, it is not known whether such changes are correlated with indices of odor perception and dementia. To investigate these issues, 12 early stage AD patients and 13 nondemented controls underwent fMRI while being exposed to each of three concentrations of lavender oil odorant. All participants were administered the University of Pennsylvania Smell Identification Test (UPSIT), the Mini-Mental State Examination (MMSE), the Mattis Dementia Rating Scale-2 (DRS-2), and the Clinical Dementia Rating Scale (CDR). The blood oxygen level-dependent (BOLD) signal at primary olfactory cortex (POC) was weaker in AD than in HC subjects. At the lowest odorant concentration, the BOLD signals within POC, hippocampus, and insula were significantly correlated with UPSIT, MMSE, DRS-2, and CDR scores. The BOLD signal intensity and activation volume within the POC increased significantly as a function of odorant concentration in the AD group, but not in the control group. These findings demonstrate that olfactory fMRI is sensitive to the AD-related olfactory and cognitive functional decline.

The relationship between iron dyshomeostasis and amyloidogenesis in Alzheimer's disease: Two sides of the same coin

The dysregulation of iron metabolism in Alzheimers disease is not accounted for in the current framework of the amyloid cascade hypothesis. Accumulating evidence suggests that impaired iron homeostasis is an early event in Alzheimers disease progression. Iron dyshomeostasis leads to a loss of function in several enzymes requiring iron as a cofactor, the formation of toxic oxidative species, and the elevated production of beta-amyloid proteins. Several common genetic polymorphisms that cause increased iron levels and dyshomeostasis have been associated with Alzheimers disease but the pathoetiology is not well understood. A full picture is necessary to explain how heterogeneous circumstances lead to iron loading and amyloid deposition. There is evidence to support a causative interplay between the concerted loss of iron homeostasis and amyloid plaque formation. We hypothesize that iron misregulation and beta-amyloid plaque pathology are synergistic in the process of neurodegeneration and ultimately cause a downward cascade of events that spiral into the manifestation of Alzheimers disease. In this review, we amalgamate recent findings of brain iron metabolism in healthy versus Alzheimers disease brains and consider unique mechanisms of iron transport in different brain cells as well as how disturbances in iron regulation lead to disease etiology and propagate Alzheimers pathology.

Reduction of magnetic field inhomogeneity artifacts in echo planar imaging with SENSE and GESEPI at high field.

Geometric distortion, signal‐loss, and image‐blurring artifacts in echo planar imaging (EPI) are caused by frequency shifts and T  2* relaxation distortion of the MR signal along the k‐space trajectory due to magnetic field inhomogeneities. The EPI geometric‐distortion artifact associated with frequency shift can be reduced with parallel imaging techniques such as SENSE, while the signal‐loss and blurring artifacts remain. The gradient‐echo slice excitation profile imaging (GESEPI) method has been shown to be successful in restoring tissue T  2* relaxation characteristics and is therefore effective in reducing signal‐loss and image‐blurring artifacts at a cost of increased acquisition time. The SENSE and GESEPI methods are complementary in artifact reduction. Combining these two techniques produces a method capable of reducing all three types of EPI artifacts while maintaining rapid acquisition time. Magn Reson Med 52:1418–1423, 2004.

Direct magnetic resonance imaging of histological tissue samples at 3.0T.

Direct imaging of a histological slice is challenging. The vast difference in dimension between planar size and the thickness of histology slices would require an RF coil to produce a uniform RF magnetic (B1) field in a 2D plane with minimal thickness. In this work a novel RF coil designed specifically for imaging a histology slice was developed and tested. The experimental data demonstrate that the coil is highly sensitive and capable of producing a uniform B1 field distribution in a planar region of histological slides, allowing for the acquisition of high‐resolution T2 images and T2 maps from a 60‐μm‐thick histological sample. The image intensity and T2 distributions were directly compared with histological staining of the relative iron concentration of the same slice. This work demonstrates the feasibility of using a microimaging histological coil to image thin slices of pathologically diseased tissue to obtain a precise one‐to‐one comparison between stained tissue and MR images. Magn Reson Med 57:835–841, 2007.

The effect of iron in MRI and transverse relaxation of amyloid-beta plaques in Alzheimer's disease

Dysregulation of neural iron is known to occur during the progression of Alzheimers disease. The visualization of amyloid‐beta (Aβ) plaques with MRI has largely been credited to rapid proton relaxation in the vicinity of plaques as a result of focal iron deposition. The goal of this work was to determine the relationship between local relaxation and related focal iron content associated with Aβ plaques. Alzheimers disease (n = 5) and control tissue (n = 3) sample slices from the entorhinal cortex were treated overnight with the iron chelator deferoxamine or saline, and microscopic gradient‐echo MRI datasets were taken. Subsequent to imaging, the same slices were stained for Aβ and iron, and then compared with regard to parametric R2* relaxation maps and gradient‐echo‐weighted MR images. Aβ plaques in both chelated and unchelated tissue generated MR hypo‐intensities and showed relaxation rates significantly greater than the surrounding tissue. The transverse relaxation rate associated with amyloid plaques was determined not to be solely a result of iron load, as much of the relaxation associated with Aβ plaques remained following iron chelation. The data indicate a dual relaxation mechanism associated with Aβ plaques, such that iron and plaque composition synergistically produce transverse relaxation.Copyright

Histological-MRI correlation in the primary motor cortex of patients with amyotrophic lateral sclerosis.

To establish the relationship between ALS histopathology and quantitative MRI metrics.

Cortical iron regulation and inflammatory response in Alzheimer's disease and APPSWE/PS1ΔE9 mice: a histological perspective

Disruption of iron homeostasis and increased glial response are known to occur in brains afflicted by Alzheimers disease (AD). While the APP/PS1 transgenic mouse model recapitulates the hallmark amyloid-beta plaque pathology of AD, it does so in a different neuronal mileu than humans. Understanding the iron characteristics and glial response of the APP/PS1 model is important when testing new treatment procedures and translating these results. Brain tissue from AD patients, APP/PS1 mice, and controls were stained for iron, H- and L-ferritin, microglia, astrocytes, Aβ40∕42, and degenerating neurons. The histological data demonstrate differences in ferritin, iron distribution, gliosis, and Aβ plaque composition between APP/PS1 and AD tissue. Specifically, an association between focal iron deposition and Aβ plaques is found ubiquitously throughout the AD tissue and is not observed in the APP/PS1 mouse model. Ferritin, microglia, and astrocyte staining show differential response patterns to amyloid plaques in AD and the APP/PS1 tissue. Aβ 40 and 42 antibody and thioflavin staining demonstrate morphological differences in plaque composition. The histological data support the hypothesis that iron distribution, iron management, and glial response histologically differ between the APP/PS1 and AD brain. Acknowledging the caveat that there are distinct plaque, iron, and glial contrasts between the AD brain and the APP/PS1 mouse is crucial when utilizing this model.

Functional MRI evidence for distinctive binding and consolidation pathways for face-name associations: analysis of activation maps and BOLD response amplitudes.

Objective: Although some of the anatomical underpinnings of learning and memory systems have been identified, there remains little understanding of how the brain moves from acquiring new information to retaining it. This study was designed to further explore and elucidate the neural mechanisms underlying encoding and memory in a common real-life task, that is, face-name associations. One possible outcome is that the tasks will recruit different neural structures mediating these processes, which can be identified through contrast analysis of activations. Alternatively, it is possible that similar anatomical regions, such as the hippocampus and parahippocampal gyrus, may be involved in both tasks. In that case, analysis of blood oxygenation level dependent (BOLD) amplitude differences between the tasks in those common neural structures may be able to detect whether physiological activation differences occur in encoding versus memory. Methods: Five healthy adult participants underwent high-field magnetic resonance imaging (MRI) while learning face-name pairs (encoding phase) and during a multiple-choice recognition task after a brief delay (memory phase). Average activation and BOLD response amplitudes in specific regions of interest and whole-brain activation maps were analyzed. Results: Common activations were observed in the encoding and recognition memory tasks in several regions of interest encompassing the medial temporal and inferior occipital regions. However, higher BOLD response amplitudes occurred in the right fusiform gyrus and the right hippocampus during encoding. In contrast, higher amplitudes were detected in the lingual gyrus bilaterally during recognition memory. Encoding activated distributed prefrontal and temporal cortical regions bilaterally, which mediate attentional, executive, language, and memory systems. Recognition memory recruited a different network of regions encompassing convergence zones in the left prefrontal cortex and the parietal-occipital-temporal region bilaterally, where multimodal visual association, language, memory, and decision-making systems interact. Conclusions: Higher BOLD response amplitudes in the right fusiform gyrus and the right hippocampus during face-name encoding suggest a potentially specific binding pathway where disparate information might be neurally linked. In contrast, the increased BOLD response in the lingual gyrus during recognition memory may indicate a key neural substrate for memory consolidation and long-term knowledge of what is learned. Whole-brain activation maps revealed task-specific differences in areas of the prefrontal, temporal, and occipital-parietal-temporal junctions as well. Findings suggest that there are distinctive anatomical and physiological nodes for face-name learning and memory within large-scale cortical-subcortical networks. Hence, lesions in fairly widespread cerebral regions may potentially disrupt specific binding and/or memory consolidation processes.

Dietary lipophilic iron alters amyloidogenesis and microglial morphology in Alzheimer's disease knock-in APP mice

Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized pathologically by amyloid beta (Aβ) deposition, microgliosis, and iron dyshomeostasis. Increased labile iron due to homeostatic dysregulation is believed to facilitate amyloidogenesis. Free iron is incorporated into aggregating amyloid peptides during Aβ plaque formation and increases potential for oxidative stress surrounding plaques. The goal of this work was to observe how brain iron levels temporally influence Aβ plaque formation, plaque iron concentration, and microgliosis. We fed humanized APPNL-F and APPNL-G-F knock-in mice lipophilic iron compound 3,5,5-trimethylhexanoyl ferrocene (TMHF) and iron deficient diets for twelve months. TMHF elevated brain iron by 22% and iron deficiency decreased brain iron 21% relative to control diet. Increasing brain iron with TMHF accelerated plaque formation, increased Aβ staining, and increased senile morphology of amyloid plaques. Increased brain iron was associated with increased plaque-iron loading and microglial iron inclusions. TMHF decreased IBA1+ microglia branch length while increasing roundness indicative of microglial activation. This body of work suggests that increasing mouse brain iron with TMHF potentiates a more human-like Alzheimers disease phenotype with iron integration into Aβ plaques and associated microgliosis.