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1.  Microbleeds in the logopenic variant of primary progressive aphasia 
Microbleeds have been associated with Alzheimer’s disease (AD), although it is unclear whether they occur in atypical presentations of AD, such as the logopenic variant of primary progressive aphasia (lvPPA). We aimed to assess the presence and clinical correlates of microbleeds in lvPPA.
Thirteen lvPPA subjects underwent 3T T2*-weighted and fluid-attenuated inversion recovery MRI and Pittsburgh Compound B (PiB) PET imaging. Microbleeds were identified on manual review and assigned a regional location. Total and regional white matter hyperintensity (WMH) burden was measured.
Microbleeds were observed in four lvPPA subjects (31%); most common in frontal lobe. Subjects with microbleeds were older, more likely female, and had a greater burden of WMH than those without microbleeds. The regional distribution of microbleeds did not match the regional distribution of WMH. All cases were PiB-positive.
Microbleeds occur in approximately 1/3 subjects with lvPPA, with older women at the highest risk.
PMCID: PMC3706560  PMID: 23562427
Logopenic variant of primary progressive aphasia; Alzheimer’s disease; microbleeds; white matter hyperintensities
2.  Preoperative assessment of meningioma stiffness by magnetic resonance elastography 
Journal of neurosurgery  2012;118(3):643-648.
To determine the potential of magnetic resonance elastography (MRE) to preoperatively assess the stiffness of meningiomas.
Thirteen subjects with meningiomas underwent a 3D brain MRE exam to measure stiffness in the tumor as well as the surrounding brain tissue. Blinded to the MRE results, the neurosurgeons made a qualitative assessment of tumor stiffness at the time of resection. The ability of MRE to predict the surgical assessment of stiffness was tested with a Spearman rank correlation.
One case was excluded due to small tumor size. In the remaining 12 cases, both tumor stiffness alone (p=0.023) and the ratio of tumor stiffness to the stiffness in the surrounding brain tissue (p=0.0032) significantly correlated with the surgeons’ qualitative assessment of tumor stiffness. The results of the MRE exam provided a stronger correlation with the surgical assessment of stiffness compared to traditional T1 and T2 weighted imaging (p=0.089), particularly when considering meningiomas of intermediate stiffness.
In this cohort, MRE was able to predict the tumor consistency at the time of surgery. Tumor stiffness as measured by MRE outperformed conventional MRI since appearance on T1 and T2 images could only accurately predict the softest and hardest meningiomas.
PMCID: PMC3920576  PMID: 23082888
meningioma; stiffness; consistency; MR elastography
3.  MRI and MRS predictors of mild cognitive impairment in a population-based sample 
Neurology  2013;81(2):126-133.
To investigate MRI and proton magnetic resonance spectroscopy (MRS) predictors of mild cognitive impairment (MCI) in cognitively normal older adults.
Subjects were cognitively normal older adults (n = 1,156) who participated in the population-based Mayo Clinic Study of Aging MRI/MRS study from August 2005 to December 2010 and had at least one annual clinical follow-up. Single-voxel MRS was performed from the posterior cingulate gyri, and hippocampal volumes and white matter hyperintensity volumes were quantified using automated methods. Brain infarcts were assessed on MRI. Cox proportional hazards regression, with age as the time scale, was used to assess the effect of MRI and MRS markers on the risk of progression from cognitively normal to MCI. Linear mixed-effects models were used to assess the effect of MRI and MRS markers on cognitive decline.
After a median follow-up of 2.8 years, 214 participants had progressed to MCI or dementia (estimated incidence rate = 6.1% per year; 95% confidence interval = 5.3%–7.0%). In univariable modeling, hippocampal volume, white matter hyperintensity volume, and N-acetylaspartate/myo-inositol were significant predictors of MCI in cognitively normal older adults. In multivariable modeling, only decreased hippocampal volume and N-acetylaspartate/myo-inositol were independent predictors of MCI. These MRI/MRS predictors of MCI as well as infarcts were associated with cognitive decline (p < 0.05).
Quantitative MRI and MRS markers predict progression to MCI and cognitive decline in cognitively normal older adults. MRS may contribute to the assessment of preclinical dementia pathologies by capturing neurodegenerative changes that are not detected by hippocampal volumetry.
PMCID: PMC3770173  PMID: 23761624
4.  Decreased Brain Stiffness in Alzheimer's Disease Determined by Magnetic Resonance Elastography 
To test patient acceptance and reproducibility of the 3D MRE brain exam using a soft vibration source, and to determine if MRE could noninvasively measure a change in the elastic properties of the brain parenchyma due to Alzheimer's disease (AD).
Materials and Methods
MRE exams were performed using an accelerated spin-echo EPI pulse sequence and stiffness was calculated with a 3D direct inversion algorithm. Reproducibility of the technique was assessed in 10 male volunteers, who each underwent 4 MRE exams separated into 2 imaging sessions. The effect of Alzheimer's disease on brain stiffness was assessed in 28 volunteers, 7 with probable AD, 14 age- and gender-matched PIB-negative (Pittsburgh Compound B, a PET amyloid imaging ligand) cognitively normal controls (CN-), and 7 age- and gender-matched PIB-positive cognitively normal controls (CN+).
The median stiffness of the 10 volunteers was 3.07 kPa with a range of 0.40 kPa. The median and maximum coefficients of variation for these volunteers were 1.71% and 3.07%. The median stiffness of the 14 CN- subjects was 2.37 kPa (0.44 kPa range) compared to 2.32 kPa (0.49 kPa range) within the CN+ group and 2.20 kPa (0.33 kPa range) within the AD group. A significant difference was found between the 3 groups (p=0.0055, Kruskal-Wallis one-way analysis of variance). Both the CN+ and CN- groups were significantly different from the AD group.
3D MRE of the brain can be performed reproducibly and demonstrates significantly reduced brain tissue stiffness in patients with AD.
PMCID: PMC3217096  PMID: 21751286
Alzheimer's disease; MR elastography; brain; stiffness
5.  Thrombogenic microvesicles and white matter hyperintensities in postmenopausal women 
Neurology  2013;80(10):911-918.
To determine the association of conventional cardiovascular risk factors, markers of platelet activation, and thrombogenic blood-borne microvesicles with white matter hyperintensity (WMH) load and progression in recently menopausal women.
Women (n = 95) enrolled in the Mayo Clinic Kronos Early Estrogen Prevention Study underwent MRI at baseline and at 18, 36, and 48 months after randomization to hormone treatments. Conventional cardiovascular risk factors, carotid intima-medial thickness, coronary arterial calcification, plasma lipids, markers of platelet activation, and thrombogenic microvesicles were measured at baseline. WMH volumes were calculated using a semiautomated segmentation algorithm based on fluid-attenuated inversion recovery MRI. Correlations of those parameters with baseline WMH and longitudinal change in WMH were adjusted for age, months past menopause, and APOE ε4 status in linear regression analysis.
At baseline, WMH were present in all women. The WMH to white matter volume fraction at baseline was 0.88% (0.69%, 1.16%). WMH volume increased by 122.1 mm3 (95% confidence interval: −164.3, 539.5) at 36 months (p = 0.003) and 155.4 mm3 (95% confidence interval: −92.13, 599.4) at 48 months (p < 0.001). These increases correlated with numbers of platelet-derived and total thrombogenic microvesicles at baseline (p = 0.03).
Associations of platelet-derived, thrombogenic microvesicles at baseline and increases in WMH suggest that in vivo platelet activation may contribute to a cascade of events leading to development of WMH in recently menopausal women.
PMCID: PMC3653211  PMID: 23408873
6.  Elevated occipital β-amyloid deposition is associated with widespread cognitive impairment in logopenic progressive aphasia 
Most subjects with logopenic primary progressive aphasia (lvPPA) have beta-amyloid (Aβ) deposition on Pittsburgh Compound B PET (PiB-PET), usually affecting prefrontal and temporoparietal cortices, with less occipital involvement.
To assess clinical and imaging features in lvPPA subjects with unusual topographic patterns of Aβ deposition with highest uptake in occipital lobe.
Thirty-three lvPPA subjects with Aβ deposition on PiB-PET were included in this case-control study. Line-plots of regional PiB uptake were created, including frontal, temporal, parietal and occipital regions, for each subject. Subjects in which the line sloped downwards in occipital lobe (lvPPA-low), representing low uptake, were separated from those where the line sloped upwards in occipital lobe (lvPPA-high), representing unusually high occipital uptake compared to other regions. Clinical variables, atrophy on MRI, hypometabolism on F18-fluorodeoxyglucose PET, and presence and distribution of microbleeds and white matter hyperintensities (WMH) were assessed.
Seventeen subjects (52%) were classified as lvPPA-high. Mean occipital PiB uptake in lvPPA-high was higher than all other regions, and higher than all regions in lvPPA-low. The lvPPA-high subjects performed more poorly on cognitive testing, including executive and visuospatial testing, but the two groups did not differ in aphasia severity. Proportion of microbleeds and WMH was higher in lvPPA-high than lvPPA-low. Parietal hypometabolism was greater in lvPPA-high than lvPPA-low.
Unusually high occipital Aβ deposition is associated with widespread cognitive impairment and different imaging findings in lvPPA. These findings help explain clinical heterogeneity in lvPPA, and suggest that Aβ influences severity of overall cognitive impairment but not aphasia.
PMCID: PMC3920541  PMID: 23946416
7.  Measuring the Characteristic Topography of Brain Stiffness with Magnetic Resonance Elastography 
PLoS ONE  2013;8(12):e81668.
To develop a reliable magnetic resonance elastography (MRE)-based method for measuring regional brain stiffness.
First, simulation studies were used to demonstrate how stiffness measurements can be biased by changes in brain morphometry, such as those due to atrophy. Adaptive postprocessing methods were created that significantly reduce the spatial extent of edge artifacts and eliminate atrophy-related bias. Second, a pipeline for regional brain stiffness measurement was developed and evaluated for test-retest reliability in 10 healthy control subjects.
This technique indicates high test-retest repeatability with a typical coefficient of variation of less than 1% for global brain stiffness and less than 2% for the lobes of the brain and the cerebellum. Furthermore, this study reveals that the brain possesses a characteristic topography of mechanical properties, and also that lobar stiffness measurements tend to correlate with one another within an individual.
The methods presented in this work are resistant to noise- and edge-related biases that are common in the field of brain MRE, demonstrate high test-retest reliability, and provide independent regional stiffness measurements. This pipeline will allow future investigations to measure changes to the brain’s mechanical properties and how they relate to the characteristic topographies that are typical of many neurologic diseases.
PMCID: PMC3847077  PMID: 24312570
8.  A Quantitative Postmortem MRI Design Sensitive to White Matter Hyperintensity Differences and their Relationship with Underlying Pathology 
White matter hyperintensities (WMHs) associate with both cognitive slowing and motor dysfunction in the neurologically normal elderly. A full understanding of the pathology underlying this clinicoradiologic finding is currently lacking in autopsy-confirmed normal brains. To determine the histopathologic basis of WMH seen on MRI, we studied the relationship between postmortem fluid-attenuated inversion recovery (FLAIR) intensity and neuropathologic markers of white matter lesions (WMLs) that correspond to WMH in cognitively normal aging brains. Samples of periventricular (n = 24), subcortical (n = 26), and normal-appearing white matter (NAWM, n = 31) from 4 clinically and pathologically-confirmed normal cases were examined. FLAIR intensity, vacuolation, and myelin basic protein (MBP) immunoreactivity loss were significantly higher in periventricular WML vs. subcortical WML; both were higher than in NAWM. The subcortical WML and NAWM had significantly less axonal loss, astrocytic burden, microglial density, and oligodendrocyte loss than the periventricular WML. Thus, vacuolation, myelin density and small vessel density contribute to the rarefaction of white matter whereas axonal density, oligodendrocyte density, astroglial burden and microglial density did not. These data suggest that the age-related loss of MBP and a decrease in small vessel density, may contribute to vacuolation of white matter. The vacuolation enables interstitial fluid to accumulate, which contributes to the prolonged T2 relaxation and elevated FLAIR intensity in the white matter.
PMCID: PMC3511604  PMID: 23147507
Digital microscopy; Fluid attenuated inversion recovery; Normal aging; Oligodendrocytes; Postmortem magnetic resonance imaging; White matter
9.  Magnetic resonance elastography of the brain in a mouse model of Alzheimer’s disease: initial results 
Magnetic resonance imaging  2012;30(4):535-539.
The increasing prevalence of Alzheimer’s disease (AD) has provided motivation for developing novel methods for assessing the disease and the effects of potential treatments. Magnetic resonance elastography (MRE) is an MRI-based method for quantitatively imaging the shear tissue stiffness in vivo. The objective of this research was to determine whether this new imaging biomarker has potential for characterizing neurodegenerative disease. Methods were developed and tested for applying MRE to evaluate the mouse brain, using a conventional large bore 3.0T MRI system. The technique was then applied to study APP-PS1 mice, a well-characterized model of AD. Five APP-PS1 mice and 8 age-matched wild-type mice were imaged immediately following sacrifice. Brain shear stiffness measurements in APP-PS1 mice averaged 22.5% lower than those for wild-type mice (P = .0031). The results indicate that mouse brain MRE is feasible at 3.0T, and brain shear stiffness has merit for further investigation as a potential new biomarker for Alzheimer’s disease.
PMCID: PMC3433281  PMID: 22326238
Alzheimer’s disease; MR elastography; Brain; Stiffness; APP-PS1
10.  Non-Stationarity in the “Resting Brain’s” Modular Architecture 
PLoS ONE  2012;7(6):e39731.
Task-free functional magnetic resonance imaging (TF-fMRI) has great potential for advancing the understanding and treatment of neurologic illness. However, as with all measures of neural activity, variability is a hallmark of intrinsic connectivity networks (ICNs) identified by TF-fMRI. This variability has hampered efforts to define a robust metric of connectivity suitable as a biomarker for neurologic illness. We hypothesized that some of this variability rather than representing noise in the measurement process, is related to a fundamental feature of connectivity within ICNs, which is their non-stationary nature. To test this hypothesis, we used a large (n = 892) population-based sample of older subjects to construct a well characterized atlas of 68 functional regions, which were categorized based on independent component analysis network of origin, anatomical locations, and a functional meta-analysis. These regions were then used to construct dynamic graphical representations of brain connectivity within a sliding time window for each subject. This allowed us to demonstrate the non-stationary nature of the brain’s modular organization and assign each region to a “meta-modular” group. Using this grouping, we then compared dwell time in strong sub-network configurations of the default mode network (DMN) between 28 subjects with Alzheimer’s dementia and 56 cognitively normal elderly subjects matched 1∶2 on age, gender, and education. We found that differences in connectivity we and others have previously observed in Alzheimer’s disease can be explained by differences in dwell time in DMN sub-network configurations, rather than steady state connectivity magnitude. DMN dwell time in specific modular configurations may also underlie the TF-fMRI findings that have been described in mild cognitive impairment and cognitively normal subjects who are at risk for Alzheimer’s dementia.
PMCID: PMC3386248  PMID: 22761880
11.  Analysis of Time Reduction Methods for Magnetic Resonance Elastography of the Brain 
Magnetic resonance imaging  2010;28(10):1514-1524.
MR elastography uses a phase-contrast MRI technique to image shear wave propagation in tissue followed by the mathematical inversion of the equations of motion governing tissue mechanics to noninvasively image tissue stiffness. This work investigates the impact of various MR sampling strategies designed to reduce acquisition times on the accuracy of MRE inversions. The results indicate that brain MRE data can be significantly truncated while maintaining a mean global stiffness error less than 10%. The results also indicate that brain MRE data can be collected in as few as 8 lines of k-space. This degree of data truncation is possible due to the relatively low spatial frequency content and low amplitude of the shear waves observed during brain MRE exams and will facilitate the design of rapid brain MRE protocols for future clinical investigations.
PMCID: PMC2988975  PMID: 20817440

Results 1-11 (11)