Faculty Bibliography

Amyloid plaques are one of the pathological hallmarks of Alzheimer's disease (AD). The visualization of amyloid plaques in the brain is important to monitor AD progression and to evaluate the efficacy of therapeutic interventions. Our group has developed several contrast agents to detect amyloid plaques in vivo using magnetic resonance microimaging (muMRI) in AD transgenic mice, where we used intra-carotid mannitol to enhance blood-brain barrier (BBB) permeability. In the present study, we used ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, chemically coupled with Abeta1-42 peptide to detect amyloid deposition along with mannitol for in vivo muMRI by femoral intravenous injection. A 3D gradient multi-echo sequence was used for imaging with a 100mum isotropic resolution. The amyloid plaques detected by T2*-weighted muMRI were confirmed with matched histological sections. Furthermore, two different quantitative analyses were used. The region of interest-based quantitative measurement of T2* values showed contrast-injected APP/PS1 mice had significantly reduced T2* values compared to wild-type mice. In addition, the scans were examined with voxel-based morphometry (VBM) using statistical parametric mapping (SPM) for comparison of contrast-injected AD transgenic and wild-type mice. The regional differences seen in VBM comparing USPIO-Abeta1-42 injected APP/PS1 and wild-type mice correlated with the amyloid plaque distribution histologically, contrasting with no differences between the two groups of mice without contrast agent injection in regions of the brain with amyloid deposition. Our results demonstrated that both approaches were able to identify the differences between AD transgenic mice and wild-type mice, after injected with USPIO-Abeta1-42. The feasibility of using less invasive intravenous femoral injections for amyloid plaque detection in AD transgenic mice facilitates using this method for longitudinal studies in the pathogenesis of AD

It has been suggested that glucose metabolism within the brain's default network is directly associated with-and may even cause-the amyloid pathology of Alzheimer's disease (AD). Here we performed 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) and [(11)C]-labeled Pittsburgh Compound B (PIB) positron emission tomography (PET) on cognitively normal elderly subjects and on AD patients and conducted quantitative regional analysis of FDG- and PIB-PET images using an automated region of interest technique. We confirmed that resting glucose metabolism within the posterior components of the brain's default network is high in normal elderly subjects and low in AD patients, which is partially in agreement with the regional pattern of PIB uptake within the default network of AD patients. However, in several regions outside the default network, glucose metabolism was high in normal elderly subjects but was not depressed in AD patients, who exhibited significantly increased PIB uptakes in these regions. In contrast, the level of resting glucose metabolism in the default network and in regions outside the default network in normal elderly subjects was significantly correlated with the level of regional PIB uptake in AD patients. These results are discussed with experimental evidence suggesting that beta amyloid production and amyloid precursor protein regulation are dependent on neuronal activity

The fourth Leon Thal Symposium (LTS2010) was convened in Toulouse, France, on November 3, 2010. This symposium reviewed design parameters that are necessary to develop comprehensive national databases on healthy aging. Such datasets offer the potential to serve as the foundation for a systems-approach to solve the dual public health problems of: (1) early detection of people who are at elevated risk for Alzheimer's disease, and (2) the development of interventions to delay onset of, or prevent, late-life dementia. The symposium considered three interrelated components of a National Database for Longitudinal Studies on Healthy Aging as follows: (a) a registry of healthy aging adults; (b) refined computer-based assessments for data gathering, including assessments of behavioral/memory changes associated with aging that are appropriate for broad use in nonexpert settings; and (c) high performance computing/supercomputer-based approaches for health data modeling and mining

Vascular risk factors affect cerebral blood flow (CBF) and cerebral vascular reactivity, contributing to cognitive decline. Hippocampus is vulnerable to both Alzheimer's disease (AD) pathology and ischemia; nonetheless, the information about the impact of vascular risk on hippocampal perfusion is minimal. Cognitively, healthy elderly (NL=18, 69.9+/-6.7 years) and subjects with mild cognitive impairment (MCI=15, 74.9+/-8.1 years) were evaluated for the Framingham cardiovascular risk profile (FCRP). All underwent structural imaging and resting CBF assessment with arterial spin labeling (ASL) at 3T magnetic resonance imaging (MRI). In 24 subjects (NL=17, MCI=7), CBF was measured after a carbon dioxide rebreathing challenge. Across all subjects, FCRP negatively correlated with hippocampal (rho=-0.41, P=0.049) and global cortical (rho=-0.46, P=0.02) vasoreactivity to hypercapnia (VR(h)). The FCRP-VR(h) relationships were most pronounced in the MCI group: hippocampus (rho=-0.77, P=0.04); global cortex (rho=-0.83, P=0.02). The FCRP did not correlate with either volume or resting CBF. The hippocampal VR(h) was lower in MCI than in NL subjects (Z=-2.0, P=0.047). This difference persisted after age and FCRP correction (F([3,20])=4.6, P=0.05). An elevated risk for vascular pathology is associated with a reduced response to hypercapnia in both hippocampal and cortical tissue. The VR(h) is more sensitive to vascular burden than either resting CBF or brain volume

Triplication of chromosome 21 in Down syndrome (DS) results in overexpression of the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A gene (DYRK1A). DYRK1A phosphorylates cytoplasmic tau protein and appears in intraneuronal neurofibrillary tangles (NFTs). We have previously shown significantly more DYRK1A-positive NFTs in DS brains than in sporadic Alzheimer disease (AD) brains. This study demonstrates a gene dosage-proportional increase in the level of DYRK1A in DS in the cytoplasm and the cell nucleus, and enhanced cytoplasmic and nuclear immunoreactivity of DYRK1A in DS. The results suggest that overexpressed DYRK1A may alter both phosphorylation of tau and alternative splicing factor (ASF). Two-dimensional electrophoresis revealed modification of ASF phosphorylation in DS/AD and AD in comparison to controls. Altered phosphorylation of ASF by overexpressed nuclear DYRK1A may contribute to the alternative splicing of the tau gene and an increase by 2.68 x of the 3R/4R ratio in DS/AD, and a several-fold increase in the number of 3R tau-positive NFTs in DS/AD subjects compared with that in sporadic AD subjects. These data support the hypothesis that phosphorylation of ASF by overexpressed DYRK1A may contribute to alternative splicing of exon 10, increased expression of 3R tau, and early onset of neurofibrillary degeneration in DS

Due to methodological difficulties related to the small size, variable distribution of hippocampal arteries, and the location of the hippocampus in the proximity of middle cranial fossa, little is known about hippocampal blood flow (HBF). We have tested the utility of a pulsed arterial spin labeling sequence based on multi-shot true fast imaging in steady precession to measure HBF in 34 normal volunteers (17 women, 17 men, 26-92 years old). Flow sensitivity to a mild hypercapnic challenge was also examined. Coregistered 3D MPRAGE sequence was used to eliminate from hippocampal and cortical regions of interest all voxel with <75% of gray matter. Large blood vessels were also excluded. HBF in normal volunteers averaged 61.2 +/- 9.0 mL/(100 g min). There was no statistically significant age or gender effect. Under a mild hypercapnia challenge (end tidal CO(2) pressure increase of 6.8 +/- 1.9 mmHg over the baseline), HBF response was 14.1 +/- 10.8 mL/(100 g min), whereas cortical gray matter flow increased by 18.0 +/- 12.2 mL/(100 g min). Flow response among women was significantly larger than in the men. The average absolute difference between two successive HBF measures was 3.6 mL/(100 g min) or 5.4%. The 3T true fast imaging in steady precession arterial spin labeling method offers a HBF measurement strategy that combines good spatial resolution, sensitivity, and minimal image distortions. Magn Reson Med, 2010. (c) 2010 Wiley-Liss, Inc

Introduction: A harmonized protocol for hippocampal MR-based segmentation is required for diagnosis and tracking of Alzheimer's disease (AD) and other disorders. A survey of segmentation protocols identified anatomical sources of heterogeneity in volume estimates. Aim: To identify differences among segmentation protocols and provide quantitative information supporting decisions for an international harmonized protocol. Methods: We selected 12 most used hippocampal tracing protocols in the AD literature for evaluation. The same rater carried out complete tracings on two MR scans (one control, one matched AD ADNI subjects) on 1.2 mm slices, using each of the 12 protocols. We arranged individual interactive web conferences with the primary author of each protocol, to check the appropriate execution of the tracing, and correct it when necessary. Landmark differences were extracted from the semantically harmonized landmarks obtained from the certified protocols (available at www.hippocampal-protocol.net). Results: The main differences between the protocols consisted in (a) inclusion/exclusion of hippocampal white matter (alveus/fimbria) (b) definition of the posterior most slice, and (c) definition of the separation between the subiculum and the parahippocampal gyrus. Heterogeneities in the definition of the boundary with the amygdala are no longer an issue due to the currently available software allowing 3D navigation. Conclusions: These results are preparatory to an international consensus for a harmonized protocol for the manual tracing of the hippocampus

Background: To quantify the impact of the differences among Magnetic Resonance Imaging (MRI)-based hippocampal segmentation protocols on volume estimates of Alzheimer's disease (AD)-related atrophy, in order to support evidence-based decisions for an internationally harmonized protocol. A harmonized procedure is required, since quantitative MRI should help diagnosis and tracking of AD. A survey of segmentation protocols allowed to operationalize the landmarks variability into segmentation units (SUs) (Figure), and their impact on volume estimates has been preliminarily quantified. Methods: A power analysis was carried out on a preliminary sample, to define the sample size allowing reliable computation. Then, we manually traced each SU within the right and left hippocampi of a larger sample of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, which included Mild Cognitive Impairment (MCI) patients who subsequently converted to AD and AD patients, all with abnormal Cerebrospinal Fluid (CSF) As levels, and controls (CTRL), with normal CSF As levels. Results: The power analysis indicated a required sample size for the quantification of SUs impact on AD-related volume differences of n=77 (31 CTRL, 23 MCI, 23 AD). So far, 40 subjects (16 CTRL, 12 MCI, 12 AD) have been traced and analyzed. The minimum hippocampal body (red SU in Figure) accounted for over 62% of AD-related volume difference across groups (left: 68.5%, right: 62%, p<0.001); the left alveus/fimbria (yellow SU in Figure) for 7.5% (p=0.01) and the right alveus/fimbria for 3% (p=0.7); the subiculum (green SUs in Figure) for 5% bilaterally (left: p=0.08; right: p=0.03); the left tail (blue SUs in Figure) for 19% (p=0.003), and the right tail for the 30% (p=0.001) of the global difference across groups. Conclusions: The informative value for identifying AD-related atrophy differs across SUs. Its quantification may help a panel of experts to define which SU should be included in a harmonized protocol. (Figure presented)

The development of prevention therapies for Alzheimer's disease (AD) would greatly benefit from biomarkers that are sensitive to subtle brain changes occurring prior to the onset of clinical symptoms, when the potential for preservation of function is at the greatest. In vivo brain imaging is a promising tool for the early detection of AD through visualization of abnormalities in brain structure, function and histopathology. Currently, Positron Emission Tomography (PET) imaging with amyloid-beta (Abeta) tracers and 2-[18F]fluoro-2-Deoxy-D-glucose (FDG) is largely utilized in the early and differential diagnosis of AD. Abeta PET tracers bind to Abeta plaques in brain, and provide an in vivo estimate of AD pathology. FDG-PET is used to measure glucose metabolism, a marker of brain activity. This paper reviews brain Abeta-and FDG-PET studies in AD patients as well as in non-demented individuals at risk for AD. We then discuss the potential of combining symptoms-sensitive FDG-PET measures with pathology-specific Abeta-PET to improve the early detection of AD. 2011 The authors and IOS Press. All rights reserved