Journal of Alzheimer's Disease - Volume 31, issue s3
The Journal of Alzheimer's Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer's disease.
The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer's disease.
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Predictive Biomarkers for Alzheimer's Disease Using State-of-the-Art Brain Imaging Techniques
Authors: Mandal, Pravat K.
DOI: 10.3233/JAD-2012-120731
Citation: Journal of Alzheimer's Disease, vol. 31, no. s3, pp. S1-S3, 2012
Magnetic Resonance Imaging Based Clinical Research in Alzheimer's Disease
Authors: Fayed, Nicolás | Modrego, Pedro J. | Salinas, Gulillermo Rojas | Gazulla, José
Abstract: Alzheimer's disease (AD) is the most common cause of dementia in elderly people in western countries. However important goals are unmet in the issue of early diagnosis and the development of new drugs for treatment. Magnetic resonance imaging (MRI) and volumetry of the medial temporal lobe structures are useful tools for diagnosis. Positron emission tomography is one of the most sensitive tests for making an early diagnosis of AD but the cost and limited availability are important caveats for its utilization. The importance of magnetic resonance techniques has increased gradually to the extent that most clinical works based on AD …use these techniques as the main aid to diagnosis. However, the accuracy of structural MRI as biomarker of early AD generally reaches an accuracy of 80%, so additional biomarkers should be used to improve predictions. Other structural MRI (diffusion weighted, diffusion-tensor MRI) and functional MRI have also added interesting contribution to the understanding of the pathophysiology of AD. Magnetic resonance spectroscopy has proven useful to monitor progression and response to treatment in AD, as well as a biomarker of early AD in mild cognitive impairment. Show more
Keywords: Alzheimer's disease, diffusion, functional, magnetic resonance, monitoring of treatment, perfusion, spectroscopy, structural image
Citation: Journal of Alzheimer's Disease, vol. 31, no. s3, pp. S5-S18, 2012
Multimodal Imaging Evidence for Axonal and Myelin Deterioration in Amnestic Mild Cognitive Impairment
Authors: Gold, Brian T. | Jiang, Yang | Powell, David K. | Smith, Charles D.
Abstract: White matter (WM) microstructural declines have been demonstrated in Alzheimer's disease and amnestic mild cognitive impairment (aMCI). However, the pattern of WM microstructural changes in aMCI after controlling for WM atrophy is unknown. Here, we address this issue through joint consideration of aMCI alterations in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, as well as macrostructural volume in WM and gray matter compartments. Participants were 18 individuals with aMCI and 24 healthy seniors. Voxelwise analyses of diffusion tensor imaging data was carried out using tract-based spatial statistics (TBSS) and voxelwise analyses of high-resolution structural data was conducted using …voxel based morphometry. After controlling for WM atrophy, the main pattern of TBSS findings indicated reduced fractional anisotropy with only small alterations in mean diffusivity/radial diffusivity/axial diffusivity. These WM microstructural declines bordered and/or were connected to gray matter structures showing volumetric declines. However, none of the potential relationships between WM integrity and volume in connected gray matter structures was significant, and adding fractional anisotropy information improved the classificatory accuracy of aMCI compared to the use of hippocampal atrophy alone. These results suggest that WM microstructural declines provide unique information not captured by atrophy measures that may aid the magnetic resonance imaging contribution to aMCI detection. Show more
Keywords: Alzheimer's disease, atrophy, diffusion tensor imaging, mild cognitive impairment
Citation: Journal of Alzheimer's Disease, vol. 31, no. s3, pp. S19-S31, 2012
Anatomical MRI and DTI in the Diagnosis of Alzheimer's Disease: A European Multicenter Study
Authors: Teipel, Stefan J. | Wegrzyn, Martin | Meindl, Thomas | Frisoni, Giovanni | Bokde, Arun L.W. | Fellgiebel, Andreas | Filippi, Massimo | Hampel, Harald | Klöppel, Stefan | Hauenstein, Karlheinz | Ewers, Michael | the EDSD study group
Abstract: Diffusion tensor imaging (DTI) detects microstructural changes of the cerebral white matter in Alzheimer's disease (AD). The use of DTI for the diagnosis of AD in a multicenter setting has not yet been investigated. We used voxel-based analysis of fractional anisotropy, mean diffusivity, and grey matter volumes from multimodal magnetic resonance imaging data of 137 AD patients and 143 healthy elderly controls collected across 9 different scanners. We compared different univariate analysis approaches to model the effect of scanner, including a linear model across all scans with a scanner covariate, a random effects model with scanner as a random variable …as well as a voxel-based meta-analysis. We found significant reduction of fractional anisotropy and significant increase of mean diffusivity in core areas of AD pathology including corpus callosum, medial and lateral temporal lobes, as well as fornix, cingulate gyrus, precuneus, and prefrontal lobe white matter. Grey matter atrophy was most pronounced in medial and lateral temporal lobe as well as parietal and prefrontal association cortex. The effects of group were spatially more restricted with random effects modeling of scanner effects compared to simple pooled analysis. All three analysis approaches yielded similar accuracy of group separation in block-wise cross-validated logistic regression. Our results suggest similar effects of center on group separation based on different analysis approaches and confirm a typical pattern of cortical and subcortical microstructural changes in AD using a large multimodal multicenter data set. Show more
Keywords: Atrophy, cortical connectivity, early diagnosis, imaging biomarker, white matter
Structural Brain Alterations before Mild Cognitive Impairment in ADNI: Validation of Volume Loss in a Predefined Antero-Temporal Region
Authors: Smith, Charles D. | Andersen, Anders H. | Gold, Brian T. | For the Alzheimer's Disease Neuroimaging Initiative
Abstract: Volume losses in the medial temporal lobe, posterior cingulated, and orbitofrontal region have been observed in Alzheimer's disease (AD). Smaller reductions in similar regions have also been reported in amnestic mild cognitive impairment (aMCI), a canonical precursor to AD. We previously demonstrated that volume loss in bilateral anteromedial temporal lobe is present at baseline in longitudinally followed normal subjects who later developed MCI or AD. In this study we compared grey matter volumes within this predefined anteromedial temporal region (AMTR) at baseline between: 1) normal subjects enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who subsequently developed cognitive complaints as …reflected in a CDR memory box score of 0.5; and 2) normal subjects who remained normal over a median of 48 months of follow-up (CDR sum of boxes 0). We found significantly decreased volume within AMTR in the ADNI memory complainers. To relate AMTR results to those from conventional anatomy, we demonstrate that volumes extracted with the ICBM amygdala region had the best correspondence with AMTR volumes. In contrast, regions that have demonstrated volume loss in frank MCI and AD in ADNI, e.g., the posterior cingulate, did not show volume loss. These findings provide independent confirmation that volume changes preceding MCI occur in AMTR, a region of overlap between amygdala and anterior hippocampus. Show more
Keywords: Alzheimer's disease neuroimaging initiative, Alzheimer's disease risk, amygdala, brain aging, hippocampus, longitudinal studies, magnetic resonance imaging, medial temporal lobe, structural neuroimaging, voxel-based morphometry
Assessment of Alzheimer's Disease Risk with Functional Magnetic Resonance Imaging: An Arterial Spin Labeling Study
Authors: Bangen, Katherine J. | Restom, Khaled | Liu, Thomas T. | Wierenga, Christina E. | Jak, Amy J. | Salmon, David P. | Bondi, Mark W.
Abstract: Functional magnetic resonance imaging (fMRI) of older adults at risk for Alzheimer's disease (AD) by virtue of their cognitive (i.e., mild cognitive impairment [MCI]) and/or genetic (i.e., apolipoprotein E [APOE] ε4 allele) status demonstrate divergent brain response patterns during memory encoding across studies. Using arterial spin labeling MRI, we examined the influence of AD risk on resting cerebral blood flow (CBF) as well as the CBF and blood oxygenation level dependent (BOLD) signal response to memory encoding in the medial temporal lobes (MTL) in 45 older adults (29 cognitively normal [14 APOE ε4 carriers and 15 noncarriers]; 16 MCI [8 …APOE ε4 carriers, 8 noncarriers]). Risk groups were comparable in terms of mean age, years of education, gender distribution, and vascular risk burden. Individuals at genetic risk for AD by virtue of the APOE ε4 allele demonstrated increased MTL resting state CBF relative to ε4 noncarriers, whereas individuals characterized as MCI showed decreased MTL resting state CBF relative to their cognitively normal peers. For percent change CBF, there was a trend toward a cognitive status by genotype interaction. In the cognitively normal group, there was no difference in percent change CBF based on APOE genotype. In contrast, in the MCI group, APOE ε4 carriers demonstrated significantly greater percent change in CBF relative to ε4 noncarriers. No group differences were found for BOLD response. Findings suggest that abnormal resting state CBF and CBF response to memory encoding may be early indicators of brain dysfunction in individuals at risk for developing AD. Show more
Keywords: Apolipoprotein E, cerebral blood flow, functional, hippocampus, magnetic resonance imaging, memory, mild cognitive impairment
Mapping of Hippocampal pH and Neurochemicals from in vivo Multi-Voxel 31P Study in Healthy Normal Young Male/Female, Mild Cognitive Impairment, and Alzheimer's Disease
Authors: Mandal, Pravat K. | Akolkar, Himanshu | Tripathi, Manjari
Abstract: Magnetic resonance spectroscopy (MRS) plays an important role in the understanding of membrane and energy metabolism. The outcome of MRS experiments helps to derive important cellular conditions (e.g., intracellular pH, energy, membrane metabolism, etc.), which are directly related to neuronal health. We present a novel multi-voxel 31 P MRS imaging experimental scheme along with an advanced 31 P signal processing technique to determine the pH and neurochemicals from both hippocampal areas in shorter time (13.2 min) for subjects (e.g. healthy young male/female, mild cognitive impairment (MCI) and Alzheimer's disease (AD)). Significant (p = 0.005) decrease of phosphomonoester (PME) and increase …of phosphodiester (PDE) (p < 0.001), γ-ATP (0.008), and PCr (p = 0.001) levels in the left hippocampus of AD patients (n = 6) compared to the control subjects (n = 12) were found based on post-hoc ANOVA. On the other hand, in the right hippocampus, decrease in PME (p = 0.008) and increase in PDE (p < 0.001) were significant between AD patients and controls. In case of AD subjects, pH in the left hippocampus is increased towards alkaline side compared to MCI but did not reach statistical significance level. The pH (left hippocampus) in AD is found to be negatively correlated (r = −0.829, p = 0.042) with PCr level (left hippocampus) in AD subjects. In the left hippocampus, the increase in pH to alkaline range (in normal aging, pH is decreased to acidic range) along with statistically significant increments of PCr, γ-ATP, and PDE as well as decrease of PME in AD subjects provide extremely crucial clinical information, which can be used as biomarker for AD and potentially aid in the diagnosis. Show more
Keywords: Alzheimer's disease, hippocampus, intracellular pH, mild cognitive impairment, normal subjects, multi-voxel 31P spectroscopy, phosphodiester, phosphomonoester, statistical significance
Proton and Phosphorus Magnetic Resonance Spectroscopy of a Mouse Model of Alzheimer's Disease
Authors: Mlynárik, Vladimír | Cacquevel, Matthias | Sun-Reimer, Lili | Janssens, Sharon | Cudalbu, Cristina | Lei, Hongxia | Schneider, Bernard L. | Aebischer, Patrick | Gruetter, Rolf
Abstract: The development of new diagnostic criteria for Alzheimer's disease (AD) requires new in vivo markers reflecting early pathological changes in the brain of patients. Magnetic resonance (MR) spectroscopy has been shown to provide useful information about the biochemical changes occurring in AD brain in vivo. The development of numerous transgenic mouse models of AD has facilitated the evaluation of early biomarkers, allowing researchers to perform longitudinal studies starting before the onset of the pathology. In addition, the recent development of high-field animal scanners enables the measurement of brain metabolites that cannot be reliably quantified at lower magnetic fields. In this …report, we studied a new transgenic mouse model of AD, the 5xFAD model, by in vivo proton and phosphorus MR spectroscopy. This model, which is characterized by an early-onset and a robust amyloid pathology, developed changes in the neurochemical profile, which are typical in the human disease, i.e., an increase in myo-inositol and a decrease in N-acetylaspartate concentrations, as early as in the 40th week of age. In addition, a significant decrease in the γ-aminobutyrate concentration was observed in transgenic mice at this age compared to controls. The pseudo-first-order rate constant of the creatine kinase reaction as well as relative concentrations of phosphorus-containing metabolites were not changed significantly in the 36 and 72-week old transgenic mice. Overall, these results suggest that mitochondrial activity in the 5 × FAD mice is not substantially affected but that the model is relevant for studying early biomarkers of AD. Show more
Keywords: 5xFAD, Alzheimer's disease, in vivo NMR spectroscopy, metabolic profile, transgenic mice
Handling Macromolecule Signals in the Quantification of the Neurochemical Profile
Authors: Cudalbu, Cristina | Mlynárik, Vladimir | Gruetter, Rolf
Abstract: In vivo localized proton magnetic resonance spectroscopy (1 H MRS) became a powerful and unique technique to non-invasively investigate brain metabolism of rodents and humans. The main goal of 1 H MRS is the reliable quantification of concentrations of metabolites (neurochemical profile) in a well-defined region of the brain. The availability of very high magnetic field strengths combined with the possibility of acquiring spectra at very short echo time have dramatically increased the number of constituents of the neurochemical profile. The quantification of spectra measured at short echo times is complicated by the presence of macromolecule signals of particular importance …at high magnetic fields. An error in the macromolecule estimation can lead to substantial errors in the obtained neurochemical profile. The purpose of the present review is to overview methods of high field 1 H MRS with a focus on the metabolite quantification, in particular in handling signals of macromolecules. Three main approaches of handling signals of macromolecules are described, namely mathematical estimation of macromolecules, measurement of macromolecules in vivo, and direct acquisition of the in vivo spectrum without the contribution of macromolecules. Show more
Keywords: In vivo short echo time 1H MRS, macromolecule contribution, quantification of neurochemical profile
Citation: Journal of Alzheimer's Disease, vol. 31, no. s3, pp. S101-S115, 2012
Visuospatial Perception: An Emerging Biomarker for Alzheimer's Disease
Authors: Mandal, Pravat K. | Joshi, Jitesh | Saharan, Sumiti
Abstract: In recent years, the focus of research on Alzheimer's disease (AD) has shifted toward finding reliable diagnostic biomarkers that enable accurate detection of mild cognitive impairment (MCI) as well as AD. Functional magnetic resonance imaging (fMRI) has the potential to identify functional changes in the preclinical stages of AD. In addition to the cardinal deficits in memory, deficits in visuospatial cognition are pervasive in AD. Recent neurophysiological and imaging studies have revealed that changes in visuospatial perception (VSP) functions can be detected in the early stages of AD. This review highlights the scope of VSP functional alterations as a biomarker …for AD. We describe the neuroanatomical regions involved in the processing of various VSP tasks, and discuss the effect of AD on these regions from a pathological as well as a functional point of view. A comprehensive synopsis of the existing fMRI literature that has assessed VSP in patients with MCI and AD has been provided. The diagnostic scope of monitoring the brain activation correlates of VSP processing in AD is discussed in terms of the key advantages of utilizing VSP-related deficits in AD for early detection and longitudinal tracking of AD. Show more
Keywords: Alzheimer's disease, biomarker, functional magnetic resonance imaging, mild cognitive impairment, visuospatial perception