Diffusion tensor imaging (DTI) can reveal detailed white matter anatomy and has the potential to detect abnormalities in specific white matter structures. Such detection and quantification are, however, not straightforward. The voxel-based analysis after image normalization is one of the most widely used methods for quantitative image analyses. To apply this approach to DTI, it is important to examine if structures in the white matter are well registered among subjects, which would be highly dependent on employed algorithms for normalization. In this paper, we evaluate the accuracy of normalization of DTI data using a highly elastic transformation algorithm, called large deformation diffeomorphic metric mapping. After simulation-based validation of the algorithm, DTI data from normal subjects were used to measure the registration accuracy. To examine the impact of morphological abnormalities on the accuracy, the algorithm was also tested using data from Alzheimer's disease (AD) patients with severe brain atrophy. The accuracy level was measured by using manual landmark-based white matter matching and surface-based brain and ventricle matching as gold standard. To improve the accuracy level, cascading and multicontrast approaches were developed. The accuracy level for the white matter was 1.88 ± 0.55 and 2.19 ± 0.84 mm for the measured locations in the controls and patients, respectively.

Background The fornix is the predominant outflow tract of the hippocampus, a brain region known to be affected early in the course of Alzheimer’s disease (AD). The aims of the present study were to: 1) examine the cross-sectional relationship between fornix DTI measurements (fractional anisotropy (FA), and mean (MD), axial (DA) and radial (DR) diffusivities), hippocampal volume, and memory performance, and 2) compare fornix DTI measures to hippocampal volumes as predictors of progression and transition from amnestic mild cognitive impairment (MCI) to AD dementia. Methods 23 MCI participants with baseline hippocampal volumetry and diffusion tensor imaging received detailed evaluations at baseline, 3, 6, 12 months, and 2.5 years. Six participants converted to AD over the follow-up. Fornix and posterior cingulum DTI measurements and hippocampal volumes were ascertained using manual measures. Random effects models assessed each of the neuroimaging measures as predictors of decline on the MMSE, CDR-Sum of boxes and Memory z-scores; ROC analyses examined the predictive value for conversion to AD. Results There was a significant correlation between fornix FA and hippocampal volumes. However, only the fornix measurements (FA, MD, DR, DA) were cross-sectionally correlated with memory z-scores. Both fornix FA and hippocampal volumes were predictive of memory decline. Individually, fornix FA and MD and hippocampal volumes were very good predictors of progression with likelihood ratios>83, and better than 90% accuracy. Conclusion Fornix FA both cross-sectionally correlated with and longitudinally predicted memory decline and progression to AD. Manually-drawn fornix ROI shows comparable promise to hippocampal volume as a predictive biomarker of progression and warrants replication in a larger study.

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The functional magnetic resonance imagery responses of declarative memory tasks in the medial temporal lobe (MTL) are examined by using large deformation diffeomorphic metric mapping (LDDMM) to remove anatomical variations across subjects. LDDMM is used to map the structures of the MTL in multiple subjects into extrinsic atlas coordinates; these same diffeomorphic mappings are used to transfer the corresponding functional data activation to the same extrinsic coordinates. The statistical power in the averaged LDDMM mapped signals is significantly increased over conventional Talairach-Tournoux averaging. Activation patterns are highly localized within the MTL. Whereas the present demonstration has been aimed at enhancing alignment within the MTL, this technique is general and can be applied throughout the brain.computational anatomy ͉ functional MRI R ecent developments in observing the activation of brain regions by means of functional magnetic resonance imagery (fMRI) while different tasks are being processed are now providing a clear look at the working of the marvelous machinery of the brain. Such studies are expected to reveal an in-depth understanding of the intricate and effortless processing humans can perform while they go about their daily lives. Our own efforts in fMRI of the brain have focused on the study of the medial temporal lobe (MTL) during memory encoding and retrieval (1). Since the initial report of patient H.M. (2), research on human amnesic patients and on animal models of amnesia (see ref. 3 for review) has shown that structures in the medial portions of the temporal lobe, including the hippocampal region (CA fields of the hippocampus proper, dentate gyrus, and subiculum), the entorhinal cortex, the perirhinal cortex, and the parahippocampal cortex, play a vital role in declarative memory. Although it is clear that these structures, often referred to as the ''MTL memory system'' (4), play a vital and selective role in declarative memory, and although the connectivity of the system is relatively well understood (5), the precise contribution that each structure makes in the service of declarative memory is not well understood. With its relatively fine resolution (3-4 mm 3 ), reasonably high sample rate (1-2 s per sample), and ability to isolate activity associated with specific trial types of interest or associated with specific behaviors, fMRI holds the promise of being able to make a significant contribution to our understanding of the roles of the various structures within the MTL.The major difficulty for our work on active memory is that structures in the MTL demonstrate significant variability across individuals (6, 7). When aligned to the standard atlas of Talairach and Tournoux (8), this variability is both global and local, resulting in poor overlap across individuals, leading to reduced statistical power and reduced confidence in the location of any observed activity in extrinsic coordinates. More generally, we would argue that the confounding nature of human anatomical variability ...

Background-A blood-based biomarker of Alzheimer disease (AD) would be superior to CSF and neuroimaging measures in terms of cost, invasiveness and feasibility for repeated measures. We previously reported blood ceramides varied in relation to timing of memory impairment in a population-based study. The present objective was to examine whether plasma ceramides varied by AD severity in a well-characterized clinic sample and were associated with cognitive decline and hippocampal volume loss over one year.Methods-Participants included 25 normal controls (NC), 17 amnestic Mild Cognitive Impairment (MCI), and 21 early probable AD. A thorough neuropsychological battery and neuroimaging with hippocampal volume determination were conducted at baseline and one year later. Plasma ceramides were assayed at baseline using HPLC-coupled electrospray ionization tandem mass spectrometry. : 443-326-5174, Fax: 410-550-1407, mmielke1@jhmi.edu. Disclosure: All authors report no conflicts of interest. The corresponding author had full access to all the data in the study and had final responsibility of the decision to submit for publication.Disclosure Statement: While funding for the neuroimaging and participant follow-up was partially obtained through a grant from GlaxoSmithKline, the authors had access to the data at all times and retain the data. Funding for the plasma lipids were obtained from NIH grants. All authors report no conflicts of interests with regards to GlaxoSmithKline or any other organization. All participants provided informed consent and the study was approved by the Johns Hopkins University Institutional Review Board.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Results-While all saturated ceramides were lower in MCI compared to AD at baseline, Ceramides C22:0 and C24:0 were significantly lower in the MCI group compared to both NC and AD groups (p<0.01). Ceramide levels did not differ (p>0.05) in AD versus NC. There were no cross-sectional associations between ceramides C22:0 and C24:0 and either cognitive performance or hippocampal volume among any group. However, among the MCI group, higher baseline ceramide C22:0 and C24:0 levels were predictive of cognitive decline and hippocampal volume loss one year later. NIH Public AccessAuthor Manuscript Alzheimers Dement. Author manuscript; available in PMC 2011 September 1. Conclusion-Resultssuggest that very long-chain plasma ceramides C22:0 and C24:0 are altered in MCI and predict memory loss and right hippocampal volume loss among subjects with MCI. These plasma ceramides may be early indicators of AD progression.