Hervé Barjat

Longitudinal regional brain volume changes quantified in normal aging and Alzheimer's APP × PS1 mice using MRI

In humans, mutations of amyloid precursor protein (APP) and presenilins (PS) 1 and 2 are associated with amyloid deposition, brain structural change and cognitive decline, like in Alzheimers disease (AD). Mice expressing these proteins have illuminated neurodegenerative disease processes but, unlike in humans, quantitative imaging has been little used to systematically determine their effects, or those of normal aging, on brain structure in vivo. Accordingly, we investigated wildtype (WT) and TASTPM mice (expressing human APP(695(K595N, M596L)) x PS1(M146V)) longitudinally using MRI. Automated global and local image registration, allied to a standard digital atlas, provided pairwise segmentation of 13 brain regions. We found the mature mouse brain, unlike in humans, enlarges significantly from 6-14 months old (WT 3.8+/-1.7%, mean+/-SD, P<0.0001). Significant changes were also seen in other WT brain regions, providing an anatomical benchmark for comparing other mouse strains and models of brain disorder. In TASTPM, progressive amyloidosis and astrogliosis, detected immunohistochemically, reflected even larger whole brain changes (5.1+/-1.4%, P<0.0001, transgenexage interaction P=0.0311). Normalising regional volumes to whole brain measurements revealed significant, prolonged, WT-TASTPM volume differences, suggesting transgene effects establish at <6 months old of age in most regions. As in humans, gray matter-rich regions decline with age (e.g. thalamus, cerebral cortex and caudoputamen); ventricles and white matter (corpus callosum, corticospinal tract, fornix system) increase; in TASTPMs such trends often varied significantly from WT (especially hippocampus). The pervasive, age-related structural changes between WT and AD transgenic mice (and mouse and human) suggest subtle but fundamental species differences and AD transgene effects.

Wavelet-based cluster analysis: data-driven grouping of voxel time courses with application to perfusion-weighted and pharmacological MRI of the rat brain

MRI time series experiments produce a wealth of information contained in two or three spatial dimensions that evolve over time. Such experiments can, for example, localize brain response to pharmacological stimuli, but frequently the spatiotemporal characteristics of the cerebral response are unknown a priori and variable, and thus difficult to evaluate using hypothesis-based methods alone. Here we used features in the temporal dimension to group voxels with similar time courses based on a nonparametric discrete wavelet transform (DWT) representation of each time course. Applying the DWT to each voxel decomposes its temporal information into coefficients associated with both time and scale. Discarding scales in the DWT that are associated with high-frequency oscillations (noise) provided a straight-forward data reduction step and decreased the computational burden. Optimization-based clustering was then applied to the remaining wavelet coefficients in order to produce a finite number of voxel clusters. This wavelet-based cluster analysis (WCA) was evaluated using two representative classes of MRI neuroimaging experiments. In perfusion-weighted MRI, following occlusion of the middle cerebral artery (MCAO), WCA differentiated healthy tissue and different regions within the ischemic hemisphere. Following an acute cocaine challenge, WCA localized subtle differences in the pharmacokinetic profile of the cerebral response. We conclude that WCA provides a robust method for blind analysis of time series image data.

Analysis of serial magnetic resonance images of mouse brains using image registration.

The aim of this paper is to investigate techniques that can identify and quantify cross-sectional differences and longitudinal changes in vivo from magnetic resonance images of murine models of brain disease. Two different approaches have been compared. The first approach is a segmentation-based approach: Each subject at each time point is automatically segmented into a number of anatomical structures using atlas-based segmentation. This allows cross-sectional and longitudinal analyses of group differences on a structure-by-structure basis. The second approach is a deformation-based approach: Longitudinal changes are quantified by the registration of each subjects follow-up images to that subjects baseline image. In addition the baseline images can be registered to an atlas allowing voxel-wise analysis of cross-sectional differences between groups. Both approaches have been tested on two groups of mice: A transgenic model of Alzheimers disease and a wild-type background strain, using serial imaging performed over the age range from 6-14 months. We show that both approaches are able to identify longitudinal and cross-sectional differences. However, atlas-based segmentation suffers from the inability to detect differences across populations and across time in regions which are much smaller than the anatomical regions. In contrast to this, the deformation-based approach can detect statistically significant differences in highly localized areas.

Pharmacological fMRI - Challenges in Analysing Drug-Induced Single-Event BOLD Responses

The interest in BOLD contrast based phMRI is likely to increase in the coming years, but detecting a direct modulation of regional brain activity by drugs presents a challenging problem. Based on in-vivo MRI and simulations we highlight some of the issues in detecting especially small BOLD signals in rat phMRI experiments.

Deformation based morphometry analysis of serial magnetic resonance images of mouse brains

Deformation based morphometry is used to detect differences in in-vivo Magnetic Resonance Image (MRI) of the mouse brain obtained from two transgenic strains: TASTPM mice that over-express proteins associated with Alzheimers disease, and wild-type mice. MRI was carried out at four time points. We compare two different methods to detect group differences in the longitudinal and cross-sectional data. Both methods are based on non-rigid registration of the images to a mouse brain atlas. The whole brain volume measurements on 27 TASTPM and wild-type animals are reproducible to within 0.4% of whole brain volume. The agreement between different methods for measuring volumes in a serial study is shown. The ability to quantify changes in growth between strains in whole brain, hippocampus and cerebral cortex is demonstrated.

Deformation based morphmetry and atlas based label segmentation: Application to serial mouse brain images

The aim of this paper is to investigate techniques that can identify and quantify longitudinal changes in vivo from magnetic resonance (MR) images of murine models of brain disease. Two different approaches have been compared. The first approach is a segmentation-based approach: Each subject at each time point is automatically segmented into a number of anatomical structures using atlas-based segmentation. This allows longitudinal analyses of group differences on a structure-by-structure basis. The second approach is a deformation-based approach: Longitudinal changes are quantified via registration of each subjects follow-up images to that subjects baseline image. Both approaches have been tested on two groups of mice: A transgenic model of Alzheimers disease and a wild-type background strain, using serial imaging performed over the age range from 6-14 months. We show that both approaches are able to identify longitudinal differences. However, atlas- based segmentation suffers from the inability to detect differences across populations and across time in regions which are much smaller than the anatomical regions. In contrast to this, the deformation-based approach can detect statistically significant differences in highly localized areas.

AbstractAlzheimer’s imaging consortium presentation: Poster presentation: PosterIC-P-124: Pharmacological MRI of H3 receptor antagonist GSK189254 in the rat brain

ratio, measured in most cases at two levels which were then averaged. Results: Bicaudate and biatrial ratios (mean SD, range) were 0.160 0.038 (0.07-0.26) and 0.242 056 (0.10-0.37). Average decline in mMMS was 3.46 points/year. Using GEE analysis, we found a significant relationship between bicaudate (p 0.001) and biatrial (p 0.007) atrophy scores and the rate of cognitive decline. Decline in mMMS was 0.41 (bicaudate) and 0.19 (biatrial) mMMS points/percentage point of atrophy /year, or about 14% and 18% increased speeds of decline per percentage point of atrophy. These relationships remained significant, even with adjustments for baseline mMMS, age, sex, education, cardiovascular risk factors, and apoE4. Conclusions: Brain atrophy is associated with increased rapidity of cognitive decline in AD. This association does not appear to relate to disease severity at baseline, nor apoE, age, or cardiovascular risk factors. AD may progress at different rates in different individuals.

P1-447: Pharmacological MRI of H3 receptor antagonist GSK189254 in the rat brain

Purpose: To evaluate the safety and efficacy of oxcarbazepine in the treatment of Alzheimer’s disease (AD) patients who exhibit hypersexual behavior. Methods: In a cross-sectional study, all patients with AD being treated with oxcarbazepine for hypersexual behaviors were evaluated. All patients resided in a special care unit as part of an assisted living facility. All participants fulfilled the DSM-IV and NINCDS-ADRDA criteria for possible AD. There were no exclusion criteria. Treatment was started at 150 mg/day, and if no improvement, the dose was titrated by 150 mg/day in two divided doses. Titration stopped once the patient’s behavior was controlled, or a maximum dose of 900 mg/day was reached. Follow up blood chemistries for possible hyponatremia were performed bi-monthly. Results: Eleven male patients were evaluated. All received other medications to control hypersexual behavior prior to the study. Information regarding each patient’s behavioral status was obtained from employed caregivers at the assisted living facility. Caregivers were certified nurse aides who had direct patient contact and covered a 24 hour period of time. Four of the patients evaluated also demonstrated occasional aggressive behaviors. Efficacy was reported in all patients after two weeks of treatment. Average effective dose for treatment was 600 750 mg/day in two divided doses. No adverse events were reported. Blood chemistries were unchanged. Conclusion: Oxcarbazepine treatment for hypersexual behavior in AD patients was effective and well tolerated.