Journal of Alzheimer's Disease - Volume 26, issue s3

Authors: Oishi, Kenichi | Mielke, Michelle M. | Albert, Marilyn | Lyketsos, Constantine G. | Mori, Susumu

Article Type: Research Article

Abstract: DTI is one of the most effective MR tools for the investigation of the brain anatomy. In addition to the gray matter, histopathological studies indicate that white matter is also a good target for both the early diagnosis of AD and for monitoring disease progression, which motivates us to use DTI to study AD patients in vivo. There are already a large amount of studies reporting significant differences between AD patients and controls, as well as to predict progression of disease in symptomatic non-demented individuals. Application of these findings in clinical practice remains to be demonstrated.

Keywords: Alzheimer's disease, mild cognitive impairment, white matter, diffusion tensor imaging, clinical application

DOI: 10.3233/JAD-2011-0007

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 287-296, 2011

Authors: Yassa, Michael A.

Article Type: Research Article

Abstract: Diffusion tensor imaging is capable of resolving large fiber bundles (e.g. the corpus callosum) and has been quite informative in understanding the overall structural connectivity of the brain. Recent data has shown that traditional resolution limitations can be exceeded in humans in vivo to submillimeter resolution. This chapter discusses these new techniques, and specific applications to small pathways such as the perforant path in the medial temporal lobe. High-resolution diffusion tensor imaging is a promising new tool that can be used to discover novel biomarkers for Alzheimer's disease and other disorders. It allows for a much more detailed investigation of …brain white matter than previously possible, perhaps offering clues into the first signs of synaptic deterioration that may precede frank neuronl loss. Although these methods are still in their infancy and many challenges have to be overcome before they can be used in a clinical fashion, results so far have been promising. Challenges and future directions are discussed in detail. Show more

Keywords: Hippocampus, perforant path, diffusion tensor imaging, biomarkers, Alzheimer's disease, aging, entorhinal cortex

DOI: 10.3233/JAD-2011-0005

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 297-305, 2011

Authors: Westman, Eric | Wahlund, Lars-Olof | Foy, Catherine | Poppe, Michaela | Cooper, Allison | Murphy, Declan | Spenger, Christian | Lovestone, Simon | Simmons, Andrew

Article Type: Research Article

Abstract: Alzheimer's disease is the most common form of neurodegenerative disorder and early detection is of great importance if new therapies are to be effectively administered. We have investigated whether the discrimination between early Alzheimer's disease (AD) and elderly healthy control subjects can be improved by adding magnetic resonance spectroscopy (MRS) measures to magnetic resonance imaging (MRI) measures. In this study 30 AD patients and 36 control subjects were included. High resolution T1-weighted axial magnetic resonance images were obtained from each subject. Automated regional volume segmentation and cortical thickness measures were determined for the images. 1 H MRS was acquired from …the hippocampus and LCModel was used for metabolic quantification. Altogether, this yielded 58 different volumetric, cortical thickness and metabolite ratio variables which were used for multivariate analysis to distinguish between subjects with AD and Healthy controls. Combining MRI and MRS measures resulted in a sensitivity of 97% and a specificity of 94% compared to using MRI or MRS measures alone (sensitivity: 87%, 76%, specificity: 86%, 83% respectively). Adding the MRS measures to the MRI measures more than doubled the positive likelihood ratio from 6 to 17. Adding MRS measures to a multivariate analysis of MRI measures resulted in significantly better classification than using MRI measures alone. The method shows strong potential for discriminating between Alzheimer's disease and controls. Show more

Keywords: MRS, MRI, OPLS, AD, multivariate analysis

DOI: 10.3233/JAD-2011-0028

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 307-319, 2011

Authors: Reiman, Eric M. | Langbaum, Jessica B.S. | Fleisher, Adam S. | Caselli, Richard J. | Chen, Kewei | Ayutyanont, Napatkamon | Quiroz, Yakeel T. | Kosik, Kenneth S. | Lopera, Francisco | Tariot, Pierre N.

Article Type: Research Article

Abstract: There is an urgent need to find effective presymptomatic Alzheimer's disease (AD) treatments that reduce the risk of AD symptoms or prevent them completely. It currently takes too many healthy people, too much money and too many years to evaluate the range of promising presymptomatic treatments using clinical endpoints. We have used brain imaging and other measurements to track some of the earliest changes associated with the predisposition to AD. We have proposed the Alzheimer's Prevention Initiative (API) to evaluate investigational amyloid-modifying treatments in healthy people who, based on their age and genetic background, are at the highest imminent risk …of developing symptomatic AD using brain imaging, cerebrospinal fluid (CSF), and cognitive endpoints. In one trial, we propose to study AD-causing presenilin 1 [PS1] mutation carriers from the world's largest early-onset AD kindred in Antioquia, Colombia, close to their estimated average age at clinical onset. In another trial, we propose to study apolipoprotein E (APOE) ε4 homozygotes (and possibly heterozygotes) close to their estimated average age at clinical onset. The API has several goals: 1) to evaluate investigational AD-modifying treatments sooner than otherwise possible; 2) to determine the extent to which the treatment's brain imaging and other biomarker effects predict a clinical benefit—information needed to help qualify biomarker endpoints for use in pivotal prevention trials; 3) to provide a better test of the amyloid hypothesis than clinical trials in symptomatic patients, when these treatments may be too little too late to exert their most profound effect; 4) to establish AD prevention registries needed to support these and other presymptomatic AD trials; and 5) to give those individuals at highest imminent risk of AD symptoms access to the most promising investigational treatments in clinical trials. Show more

Keywords: Brain imaging, cerebral spinal fluid, biomarkers, surrogate markers, presymptomatic Alzheimer's disease, early-onset Alzheimer's disease, late-onset Alzheimer's disease, presenilin 1, apolipoprotein E, clinical trials

DOI: 10.3233/JAD-2011-0059

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 321-329, 2011

Authors: Ashford, J.W. | Adamson, M. | Beale, T. | La, D. | Hernandez, B. | Noda, A. | Rosen, A. | O'Hara, R. | Fairchild, J. K. | Spielman, D. | Yesavage, J.A.

Article Type: Research Article

Abstract: Objectives: Magnetic Resonance Spectroscopy (MRS) may provide a precise and reliable assessment of the extent and severity of neural tissue loss caused by various diseases. In particular, the N-Acetyl Aspartate (NAA) and Creatine (Cr) ratio has been found to be an indicator of the degree of neuronal loss in Alzheimer's disease (AD). Memantine is thought to benefit the AD brain by stabilizing the NMDA receptors on neurons in turn reducing excitotoxicity. Despite its effectiveness in treating moderate to severe AD, memantine has not had similar success in the treatment of mildly demented AD patients. The objective of this study was …to test whether memantine would slow or prevent the loss of neurons in mild to moderate AD patients. Methods: A double-blind placebo-controlled study was designed to measure the effect of a year-long course of memantine in patients with a probable AD diagnosis with mild to moderate dementia. The primary outcome measure was stipulated to be change in MRS NAA/Cr ratio in inferior parietal cortex in memantine relative to the placebo treatment condition. The secondary outcome measures were changes in cognitive and function scale scores. Results: This pilot study failed to demonstrate a benefit of memantine on the primary outcome measure, the inferior parietal NAA/Cr ratio, or the secondary outcome measures. Conclusions: More studies are needed to determine the effect of memantine on regions of the brain significantly affected by AD pathology. Show more

Keywords: Alzheimer disease, dementia, magnetic resonance spectroscopy, memantine, cognition, N-acetylaspartate, creatine

DOI: 10.3233/JAD-2011-0021

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 331-336, 2011

Authors: Förster, Stefan | Buschert, Verena C. | Teipel, Stefan J. | Friese, Uwe | Buchholz, Hans-Georg | Drzezga, Alexander | Hampel, Harald | Bartenstein, Peter | Buerger, Katharina

Article Type: Research Article

Abstract: The effect of cognitive intervention on brain metabolism in AD is largely unexplored. Therefore, we aimed to investigate cognitive parameters and 18 FDG PET to test for effects of a cognitive intervention in patients with aMCI or mild AD. Patients with aMCI (N = 24) or mild AD (N = 15) were randomly assigned either to cognitive intervention groups (IGs), receiving weekly sessions of group-based multicomponent cognitive intervention, or active control groups (CGs), receiving pencil-paper exercises for self-study. We obtained resting-state FDG-PET scans and neuropsychological testing at baseline and after six-months. Normalized FDG-PET images were analyzed using voxel-based SPM5 approaches …to determine longitudinal changes, group-by-time interactions and correlations with neuropsychological outcome parameters. Primary global cognitive outcome was determined by analyses of covariance with MMSE and ADAS-cog scores as dependent measures. Both, aMCI and AD subgroups of CGs showed widespread bilateral cortical declines in FDG uptake, while the AD subgroup of IGs showed discrete decline or rather no decline in case of the aMCI subgroup. Group by time analyses revealed strongest attenuation of metabolic decline in the aMCI subgroup of the IGs, involving left anterior temporal pole and anterior cingulate gyrus. However, correlation analyses revealed only weak non-significant associations between increased FDG uptake and improvement in primary or secondary outcome parameters. Concurrently, there was significant improvement in global cognitive status in the aMCI subgroup of the IGs. A six-month cognitive intervention imparted cognitive benefits in patients with aMCI, which were concurrent with an attenuated decline of glucose metabolism in cortical regions affected by neurodegenerative AD. Show more

Keywords: FDG PET, cognitive intervention, cognitive training, cognitive stimulation, Alzheimer's disease, mild cognitive impairment

DOI: 10.3233/JAD-2011-0025

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 337-348, 2011

Authors: Rosen, Allyson C. | Sugiura, Lisa | Kramer, Joel H. | Whitfield-Gabrieli, Susan | Gabrieli, John D.

Article Type: Research Article

Abstract: A randomized pilot experiment examined the neural substrates of response to cognitive training in participants with mild cognitive impairment (MCI). Participants performed exercises previously demonstrated to improve verbal memory and an active control group performed other computer activities. An auditory-verbal fMRI task was conducted before and after the two-month training program. Verbal memory scores improved significantly and left hippocampal activation increased significantly in the experimental group (gains in 5 of 6 participants) relative to the control group (reductions in all 6 participants). Results suggest that the hippocampus in MCI may retain sufficient neuroplasticity to benefit from cognitive training.

Keywords: MRI, dementia, cognition, MCI, mild cognitive impairment, fMRI, functional MRI, cognitive training, hippocampus, medial temporal lobe

DOI: 10.3233/JAD-2011-0009

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 349-357, 2011

Authors: Zhang, Ningnannan | Song, Xiaowei | Zhang, Yunting | Chen, Wei | D'Arcy, Ryan C.N. | Darvesh, Sultan | Fisk, John D. | Rockwood, Kenneth | Alzheimer's disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: A brain atrophy and lesion index (BALI) based on high-field magnetic resonance imaging (MRI) has recently been validated to evaluate structural changes in the aging brain. The present study investigated the two-year progression of brain structural deficits in people with Alzheimer's disease (AD) and mild cognitive impairment (MCI), and in healthy control older adults (HC) using the BALI rating. Methods: T1-weighted high-resolution anatomical imaging data using 3 Tesla MRI at baseline (AD = 39, MCI = 82, HC = 58) and at 24-months were obtained from the Alzheimer's disease Neuroimaging Initiative database. Lesions in various brain structures, including the …infratentorial and basal ganglia areas, and the periventricular and deep white matter and global atrophy, were evaluated and combined into the BALI scale. Results: Mean progression of brain deficits over two years was evident in all diagnostic groups (p < 0.001) and was statistically greater in MCI-AD converters than in the non-converters (p = 0.044). An increase in the BALI score was significantly associated with cognitive test scores (p = 0.008 for the Mini-Mental State Examination MMSE and p = 0.013 for the Alzheimer's Disease Assessment Scale-Cognitive Subscale ADAS-cog) in a model that adjusted for age, sex, and education. Conclusion: The BALI rating quantified the progression of brain deficits over two years, which is associated with cognitive decline. BALI ratings may be used to help summarize AD-associated structural variations. Show more

Keywords: Alzheimer's disease, aging, atrophy, cognition, lesion, visual scale

DOI: 10.3233/JAD-2011-0048

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 359-367, 2011

Authors: Ard, M. Colin | Edland, Steven D.

Article Type: Research Article

Abstract: The Alzheimer research community is actively pursuing novel biomarker and other biologic measures to characterize disease progression or to use as outcome measures in clinical trials. One product of these efforts has been a large literature reporting power calculations and estimates of sample size for planning future clinical trials and cohort studies with longitudinal rate of change outcome measures. Sample size estimates reported in this literature vary greatly depending on a variety of factors, including the statistical methods and model assumptions used in their calculation. We review this literature and suggest standards for reporting power calculation results. Regardless of the …statistical methods used, studies consistently find that volumetric neuroimaging measures of regions of interest, such as hippocampal volume, outperform global cognitive scales traditionally used in clinical treatment trials in terms of the number of subjects required to detect a fixed percentage slowing of the rate of change observed in demented and cognitively impaired populations. However, statistical methods, model assumptions, and parameter estimates used in power calculations are often not reported in sufficient detail to be of maximum utility. We review the factors that influence sample size estimates, and discuss outstanding issues relevant to planning longitudinal studies of Alzheimer's disease. Show more

Keywords: Sample size, clinical trials, Alzheimer's disease, biostatistics

DOI: 10.3233/JAD-2011-0062

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 369-377, 2011

Authors: Gao, Fu-qiang | Swartz, Richard H. | Scheltens, Philip | Leibovitch, Farrell S. | Kiss, Alex | Honjo, Kie | Black, Sandra E.

Article Type: Research Article

Abstract: Purpose: Quantification methods for white matter hyperintensities (WMH) on Magnetic Resonance Imaging are heterogeneous, deterring their application. This study compared three WMH rating scales, varying in complexity, and a volumetric method, to evaluate trade-offs between complexity and clinical utility in differentiating dementia subgroups and in correlating with cognition. Methods: WMH were rated using the Fazekas, Age-Related White Matter Changes (ARWMC) and Scheltens scales, and segmented by computational volumetry in 108 patients with Alzheimer's Disease (AD), 23 with Mild Cognitive Impairment (MCI) and 34 normal controls (NC). Global and hippocampal atrophy, age and education, were accounted for in correlations of WMH …with cognitive domains. Results: Intra- and inter-rater reliability were high (intraclass correlation coefficients = 0.88–0.97) across rating scales. WMH scores of all scales were highly correlated with volumes (Spearman r = 0.78–0.90, Ps < 0.001), as well as with each other (Spearman r = 0.86–0.91, Ps < 0.001). The Fazekas scale showed significant separation between AD, MCI and NC using non-parametric analysis, while the ARWMC and Scheltens' scales, and WMH volumes demonstrated significant correlations (standardized β = −0.19 to −0.24, Ps < 0.05) with cognitive domain scores using multivariate regression analysis, controlling for age, education, global and hippocampal atrophy in patients with AD. Conclusions: This study suggests that the degree of complexity of WMH rating scales did not affect validation against WMH volumes, but did vary in validation against cognition. The simplest scale performed best in separating cognitive subgroups, but the more complex scales and quantification correlated better with cognitive measures, especially executive function. Hence the best choice of scale depends on the particular application. Show more

Keywords: White matter hyperintensity, scales, MRI, cognition, Alzheimer's disease

DOI: 10.3233/JAD-2011-0058

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 379-388, 2011

Authors: Haller, Sven | Lovblad, Karl O. | Giannakopoulos, Panteleimon

Article Type: Research Article

Abstract: The majority of advanced neuroimaging studies implement group level analyses contrasting a group of patients versus a group of controls, or two groups of patients. Such analyses may identify for example changes in grey matter in specific regions associated with a given disease. Although such group investigations provided key contributions to the understanding of the pathological process surrounding a wide range of diseases, they are of limited utility at an individual level. Recently, there is a trend towards individual classification analyses, representing a fundamental shift of the research paradigm. In contrast to group comparisons, these latter studies do not provide …insights on vulnerable brain areas but may allow for an early (and ideally preclinical) identification of at risk individuals in routine clinical setting. One currently very popular method in this domain are support vector machines (SVM), yet this method is only one of many available methods in the field of individual classification analyses. The current manuscript reviews the fundamental properties and features of such individual level classification analyses in neurodegenerative diseases. Show more

Keywords: SVM (support vector machine), MVPA (multi voxel pattern analysis), artificial intelligence, machine learning, individual classification

DOI: 10.3233/JAD-2011-0014

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 389-394, 2011

Authors: Furney, Simon J. | Kronenberg, Deborah | Simmons, Andrew | Güntert, Andreas | Dobson, Richard J. | Proitsi, Petroula | Wahlund, Lars Olof | Kloszewska, Iwona | Mecocci, Patrizia | Soininen, Hilkka | Tsolaki, Magda | Vellas, Bruno | Spenger, Christian | Lovestone, Simon

Article Type: Research Article

Abstract: Progression of people presenting with Mild Cognitive Impairment (MCI) to dementia is not certain and it is not possible for clinicians to predict which people are most likely to convert. The inability of clinicians to predict progression limits the use of MCI as a syndrome for treatment in prevention trials and, as more people present with this syndrome in memory clinics, and as earlier diagnosis is a major goal of health services, this presents an important clinical problem. Some data suggest that CSF biomarkers and functional imaging using PET might act as markers to facilitate prediction of conversion. However, both …techniques are costly and not universally available. The objective of our study was to investigate the potential added benefit of combining biomarkers that are more easily obtained in routine clinical practice to predict conversion from MCI to Alzheimer's disease. To explore this we combined automated regional analysis of structural MRI with analysis of plasma cytokines and chemokines and compared these to measures of APOE genotype and clinical assessment to assess which best predict progression. In a total of 205 people with MCI, 77 of whom subsequently converted to Alzheimer's disease, we find biochemical markers of inflammation to be better predictors of conversion than APOE genotype or clinical measures (Area under the curve (AUC) 0.65, 0.62, 0.59 respectively). In a subset of subjects who also had MRI scans the combination of serum markers of inflammation and MRI automated imaging analysis provided the best predictor of conversion (AUC 0.78). These results show that the combination of imaging and cytokine biomarkers provides an improvement in prediction of MCI to AD conversion compared to either datatype alone, APOE genotype or clinical data and an accuracy of prediction that would have clinical utility. Show more

Keywords: Proteomics, MRI, mild cognitive impairment, Alzheimer's disease, biomarkers

DOI: 10.3233/JAD-2011-0044

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 395-405, 2011