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

Authors: Ashford, J. Wesson | Salehi, Ahmad | Furst, Ansgar | Bayley, Peter | Frisoni, Giovanni B. | Jack Jr, Clifford R. | Sabri, Osama | Adamson, Maheen M. | Coburn, Kerry L. | Olichney, John | Schuff, Norbert | Spielman, Daniel | Edland, Steven D. | Black, Sandra | Rosen, Allyson | Kennedy, David | Weiner, Michael | Perry, George

Article Type: Introduction

Abstract: This supplement to the Journal of Alzheimer's Disease contains more than half of the chapters from The Handbook of Imaging the Alzheimer Brain, which was first presented at the International Conference on Alzheimer's Disease in Paris, in July, 2011. While the Handbook contains 27 chapters that are modified articles from 2009, 2010, and 2011 issues of the Journal of Alzheimer's Disease, this supplement contains the 31 new chapters of that book and this introductory article drawn from the introductions to each section of the book. The Handbook was designed to provide a multi-level overview of the full field of brain …imaging related to Alzheimer's disease (AD) for students, clinicians, and scientists in the field. The Handbook, as well as this supplement, contains both reviews of the basic concepts of imaging, the latest developments in imaging, and various discussions and perspectives of the problems of the field and promising directions. The Introduction reviews critical issues, from clinical measurement to AD neuropathological observations, that are relevant for developing neuroimaging methodology and to which neuroimaging approaches can be applied. Sections of the Handbook and this supplement cover structural imaging (CT, MRI), imaging of cerebral blood flow, metabolism, amyloid pathology, and neurofibrillary changes (PET, SPECT), functional MRI, electro-magneto-encephalographic brain mapping, Diffusion Tensor Imaging (MRI, with tractography), and Magnetic Resonance Spectroscopy. Final sections cover longitudinal analyses (including assessment of progression and clinical endpoints), the interaction between AD and vascular pathology, and the interaction between neuroimaging and other methods, including a discussion of future directions. Show more

DOI: 10.3233/JAD-2011-0073

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 1-27, 2011

Authors: Sanchez, Martha Millan | Moghadam, Sarah | Naik, Priyanka | Martin, Kara J. | Salehi, Ahmad

Article Type: Research Article

Abstract: Hippocampal structural and functional alterations in Alzheimer's disease (AD), detected by advanced imaging methods, have been linked to significant abnormalities in multiple internal and external networks in this critical brain region. Uncovering the temporal and anatomical pattern of these network alterations would provide important clues into understanding the pathophysiology of AD and suggest new therapeutic strategies for this multi­system and prevalent disorder. Over the last decade, we have focused on studying brain structures that provide major projections to the hippocampus (HC) and the pattern of de-afferentation of this area in mouse models of AD and a related neurodegenerative disorder, i.e. …Down syndrome (DS). Our studies have revealed that major inputs into the hippocampal structure undergo significant age-dependent alterations. Studying locus coeruleus (LC), the sole source of noradrenergic terminals for the HC, it has been shown that these neurons show significant age-dependent degeneration in both mouse models of DS and AD. Furthermore, increasing noradrenergic signaling was able to restore cognitive function by improving synaptic plasticity, and possibly promoting microglia recruitment, and amyloid β (Aβ) clearance in transgenic (tg) mouse models of AD. Here, we re-examine the effects of alterations in major inputs to the hippocampal region and their structural and functional consequences in mouse models of neurodegenerative disorders. We will conclude that improving the function of major hippocampal inputs could lead to a significant improvement in cognitive function in both AD and DS. Show more

Keywords: Alzheimer's disease, amyloid precursor protein, contextual learning, Down syndrome, L-DOPS, locus coeruleus, norepinephrine, perforant path, xamoterol

DOI: 10.3233/JAD-2011-0050

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 29-47, 2011

Authors: Fennema-Notestine, Christine | Panizzon, Matthew S. | Thompson, Wesley R. | Chen, Chi-Hua | Eyler, Lisa T. | Fischl, Bruce | Franz, Carol E. | Grant, Michael D. | Jak, Amy J. | Jernigan, Terry L. | Lyons, Michael J. | Neale, Michael C. | Seidman, Larry J. | Tsuang, Ming T. | Xian, Hong | Dale, Anders M. | Kremen, William S.

Article Type: Research Article

Abstract: The presence of an ApoE ε4 allele (ε4+) increases the risk of developing Alzheimer's disease (AD). Previous studies support an adverse relationship between ε4+ status and brain structure and function in mild cognitive impairment and AD; in contrast, the presence of an ε2 allele may be protective. Whether these findings reflect disease-related effects or pre-existing endophenotypes, however, remains unclear. The present study examined the influence of ApoE allele status on brain structure solely during middle-age in a large, national sample. Participants were 482 men, ages 51–59, from the Vietnam Era Twin Study of Aging (VETSA). T1-weighted images were used in …volumetric segmentation and cortical surface reconstruction methods to measure regional volume and thickness. Primary linear mixed effects models predicted structural measures with ApoE status (ε3/3, ε2/3, ε3/4) and control variables for effects of site, non-independence of twin data, age, and average cranial vault or cortical thickness. Relative to the ε3/3 group, the ε3/4 group demonstrated significantly thinner cortex in superior frontal and left rostral and right caudal midfrontal regions; there were no significant effects of ε4 status on any temporal lobe measures. The ε2/3 group demonstrated significantly thicker right parahippocampal cortex relative to the ε3/3 group. The ApoE ε4 allele may influence cortical thickness in frontal areas, which are later developing regions thought to be more susceptible to the natural aging process. Previous conflicting findings for mesial temporal regions may be driven by the inclusion of older individuals, who may evidence preclinical manifestations of disease, and by unexamined moderators of ε4-related effects. The presence of the ε2 allele was related to thicker cortex, supporting a protective role. Ongoing follow-up of the VETSA sample may shed light on the potential for age- and disease-related mediation of the influence of ApoE allele status. Show more

Keywords: Magnetic resonance imaging, cerebral cortex, brain, frontal lobe, apolipoproteins E, apolipoprotein E2, apolipoprotein E3, apolipoprotein E4, genetic association studies, aging

DOI: 10.3233/JAD-2011-0002

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 49-60, 2011

Authors: Boccardi, Marina | Ganzola, Rossana | Bocchetta, Martina | Pievani, Michela | Redolfi, Alberto | Bartzokis, George | Camicioli, Richard | Csernansky, John G. | de Leon, Mony J. | deToledo-Morrell, Leyla | Killiany, Ronald J. | Lehéricy, Stéphane | Pantel, Johannes | Pruessner, Jens C. | Soininen, H. | Watson, Craig | Duchesne, Simon | Jack Jr, Clifford R. | Frisoni, Giovanni B.

Article Type: Research Article

Abstract: Manual segmentation from magnetic resonance imaging (MR) is the gold standard for evaluating hippocampal atrophy in Alzheimer's disease (AD). Nonetheless, different segmentation protocols provide up to 2.5-fold volume differences. Here we surveyed the most frequently used segmentation protocols in the AD literature as a preliminary step for international harmonization. The anatomical landmarks (anteriormost and posteriormost slices, superior, inferior, medial, and lateral borders) were identified from 12 published protocols for hippocampal manual segmentation ([Abbreviation] first author, publication year: [B] Bartzokis, 1998; [C] Convit, 1997; [dTM] deToledo-Morrell, 2004; [H] Haller, 1997; [J] Jack, 1994; [K] Killiany, 1993; [L] Lehericy, 1994; [M] Malykhin, …2007; [Pa] Pantel, 2000; [Pr] Pruessner, 2000; [S] Soininen, 1994; [W] Watson, 1992). The hippocampi of one healthy control and one AD patient taken from the 1.5T MR ADNI database were segmented by a single rater according to each protocol. The accuracy of the protocols' interpretation and translation into practice was checked with lead authors of protocols through individual interactive web conferences. Semantically harmonized landmarks and differences were then extracted, regarding: (a) the posteriormost slice, protocol [B] being the most restrictive, and [H, M, Pa, Pr, S] the most inclusive; (b) inclusion [C, dTM, J, L, M, Pr, W] or exclusion [B, H, K, Pa, S] of alveus/fimbria; (c) separation from the parahippocampal gyrus, [C] being the most restrictive, [B, dTM, H, J, Pa, S] the most inclusive. There were no substantial differences in the definition of the anteriormost slice. This survey will allow us to operationalize differences among protocols into tracing units, measure their impact on the repeatability and diagnostic accuracy of manual hippocampal segmentation, and finally develop a harmonized protocol. Show more

Keywords: Hippocampus, manual segmentation protocol, harmonization, anatomical landmark, Alzheimer's disease, manual tracing, medial temporal lobes, atrophy, degeneration, MRI

DOI: 10.3233/JAD-2011-0004

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 61-75, 2011

Authors: Tosun, Duygu | Schuff, Norbert | Shaw, Leslie M. | Trojanowski, John Q. | Weiner, Michael W. | the Alzheimer's Disease NeuroImaging Initiative

Article Type: Research Article

Abstract: Previously it was reported that Alzheimer's disease (AD) patients have reduced amyloid (Aβ1-42 ) and elevated total tau (t-tau) and phosphorylated tau (p-tau181p ) in the cerebro-spinal fluid (CSF), suggesting that these same measures could be used to detect early AD pathology in healthy elderly (CN) and mild cognitive impairment (MCI). In this study, we tested the hypothesis that there would be an association among rates of regional brain atrophy, the CSF biomarkers Aβ1-42 , t-tau, and p-tau181p and ApoE ε4 status, and that the pattern of this association would be diagnosis specific. Our findings primarily showed that lower …CSF Aβ1-42 and higher tau concentrations were associated with increased rates of regional brain tissue loss and the patterns varied across the clinical groups. Taken together, these findings demonstrate that CSF biomarker concentrations are associated with the characteristic patterns of structural brain changes in CN and MCI that resemble to a large extent the pathology seen in AD. Therefore, the finding of faster progression of brain atrophy in the presence of lower Aβ1-42 levels and higher p-tau levels supports the hypothesis that CSF Aβ1-42 and tau are measures of early AD pathology. Moreover, the relationship among CSF biomarkers, ApoE ε4 status, and brain atrophy rates are regionally varying, supporting the view that the genetic predisposition of the brain to amyloid and tau mediated pathology is regional and disease stage specific. Show more

Keywords: MRI, Alzheimer's disease, cerebrospinal fluid, biomarkers, cortical thickness, atrophy, ApoE

DOI: 10.3233/JAD-2011-0006

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 77-90, 2011

Authors: Kerchner, Geoffrey A.

Article Type: Research Article

Abstract: Ultra-high field 7T MRI offers superior signal-to-noise and spatial resolution relative to any other noninvasive imaging technique. By revealing fine anatomical details of the living brain, 7T MRI allows neuroimaging researchers the opportunity to observe in patients disease-related structural changes previously apparent only on postmortem tissue analysis. Alzheimer's disease (AD) is a natural subject for this technology, and I review here two AD-related applications of 7T MRI: direct visualization of cortical plaques, and high resolution hippocampal imaging. I also discuss limitations of this technology as well as expected advances that are likely to establish 7T MRI as an increasingly important …tool for the diagnosis and tracking of AD. Show more

Keywords: magnetic resonance imaging (MRI), 7-Tesla (7T), hippocampus, CA1, beta-amyloid, Alzheimer's disease, biomarker

DOI: 10.3233/JAD-2011-0023

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 91-95, 2011

Authors: Weih, Markus | Degirmenci, Ümüt | Kreil, Sebastian | Suttner, Gerald | Schmidt, Daniela | Kornhuber, Johannes | Lewczuk, Piotr | Kuwert, Torsten

Article Type: Research Article

Abstract: Nuclear medicine techniques were the first functional imaging techniques used to support the clinical diagnosis of Alzheimer's Disease (AD). Perfusion-SPECT allows registration of regional cerebral blood flow (rCBF) which is altered in a characteristic temporal-parietal pattern in AD. Numerous studies have shown the diagnostic value of reduced CBF and metabolic changes using perfusion-SPECT and FDG-PET in AD diagnosis as well as in differential diagnosis against frontotemporal dementia (FTD), dementia with Lewy-Bodies (DLB), and vascular cognitive disorders. This renders perfusion-SPECT an important piece of the puzzle (together with other diagnostic tests) by the clinician is often faced when making a final …etiologic dementia diagnosis especially between AD and FTD. A similar diagnostic value can be expected when arterial spin labeling (ASL) MRI sequence is used, but the diagnostic value has yet to be confirmed in lager studies. Recently, more pathophysiology-based biomarkers in CSF and Amyloid-PET tracers have been developed that probably have a higher diagnostic accuracy than the more indirect rCBF changes seen in perfusion-SPECT. In the current review, we describe recent advances in AD biomarkers as well as improvements in the SPECT technique. Show more

DOI: 10.3233/JAD-2011-0020

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 97-103, 2011

Authors: Furst, Ansgar J. | Lal, Rayhan A.

Article Type: Research Article

Abstract: This study used PET with the amyloid-β (Aβ) imaging agent 11 C Pittsburgh Compound-B (PIB) and the glucose metabolic tracer 18 F-fluorodeoxyglucose (FDG) to map the relationship of Aβ deposition to regional glucose metabolism in Alzheimer's disease (AD). Comparison of 13 AD patients' FDG scans with 11 healthy controls confirmed a typical temporo-parietal hypometabolic pattern in AD. In contrast, PIB distribution-volume-ratios showed a distinct pattern of specific tracer retention in fronto-temporo-parietal regions and striatum in AD with peaks in left frontal cortex, precuneus, temporal cortex, striatum and right posterior cingulate. There were no region-to-region or within region correlations between …FDG and PIB uptake in PIB positive AD patients but when the impact of Aβ load on glucose metabolism was assessed via probabilistic maps, increased amyloid burden was coupled with decreased metabolism in temporo-parietal regions and the posterior cingulate. However, importantly, severe Aβ burden was not associated with comparable metabolic decreases in large parts of the frontal lobes, the striatum and the thalamus. Show more

Keywords: Alzheimer's disease, amyloid plaques, amyloidosis, fluorodeoxyglucose, glucose metabolism, Pittsburgh compound-B

DOI: 10.3233/JAD-2011-0066

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 105-116, 2011

Authors: Barthel, Henryk | Sabri, Osama

Article Type: Research Article

Abstract: PET imaging of amyloid-β has recently emerged as a valuable biomarker to support the in vivo diagnosis of Alzheimer's disease (AD). So far, however, no tracer is available suitable for general clinical routine application. Florbetaben is a promising 18 F-labeled amyloid-β-targeted PET tracer currently in Phase2/3 clinical development. This review provides an overview on the current knowledge and future research activities on florbetaben. Recently, the first worldwide multi-center trial to test the diagnostic performance of amyloid-β PET in AD was conducted with this tracer. From this trial, a sensitivity and specificity of 80 and 91% in the discrimination between patients …with probable AD and age-matched healthy controls was reported. Ongoing florbetaben PET trials deal with correlating the in vivo PET signal to post mortem histopathology evaluation, and with investigating the value of the tracer to predict progression to AD at the stage of mild cognitive impairment. The preclinical and clinical data currently available verify florbetaben as a safe and efficacious PET tracer suitable for detection of amyloid-β deposition in the brain. The results of the ongoing trials will contribute to current knowledge on the characteristics of florbetaben, and will help to determine the future potential of florbetaben PET imaging as a visual adjunct to supplement the routine clinical “AD diagnostic toolbox”. Show more

Keywords: Alzheimer's disease, amyloid-β, PET imaging, florbetaben

DOI: 10.3233/JAD-2011-0068

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 117-121, 2011

Authors: Austin, Benjamin P. | Nair, Veena A. | Meier, Timothy B. | Xu, Guofan | Rowley, Howard A. | Carlsson, Cynthia M. | Johnson, Sterling C. | Prabhakaran, Vivek

Article Type: Research Article

Abstract: The role of hypoperfusion in Alzheimer's disease (AD) is a vital component to understanding the pathogenesis of this disease. Disrupted perfusion is not only evident throughout disease manifestation, it is also demonstrated during the pre-clinical phase of AD (i.e., mild cognitive impairment) as well as in cognitively healthy persons at high-risk for developing AD due to family history or genetic factors. Studies have used a variety of imaging modalities (e.g., SPECT, MRI, PET) to investigate AD, but with its recent technological advancements and non-invasive use of blood water as an endogenous tracer, arterial spin labeling (ASL) MRI has become an …imaging technique of growing popularity. Through numerous ASL studies, it is now known that AD is associated with both global and regional cerebral hypoperfusion and that there is considerable overlap between the regions implicated in the disease state (consistently reported in precuneus/posterior cingulate and lateral parietal cortex) and those implicated in disease risk. Debate exists as to whether decreased blood flow in AD is a cause or consequence of the disease. Nonetheless, hypoperfusion in AD is associated with both structural and functional changes in the brain and offers a promising putative biomarker that could potentially identify AD in its pre-clinical state and be used to explore treatments to prevent, or at least slow, the progression of the disease. Finally, given that perfusion is a vascular phenomenon, we provide insights from a vascular lesion model (i.e., stroke) and illustrate the influence of disrupted perfusion on brain structure and function and, ultimately, cognition in AD. Show more

Keywords: Alzheimer's disease, hypoperfusion, perfusion, stroke, mild cognitive impairment, ASL, MRI, vascular risk factors

DOI: 10.3233/JAD-2011-0010

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 123-133, 2011