THE CLINICAL SPECTRUM OF ALZHEIMER’S DISEASE – THE CHARGE TOWARD COMPREHENSIVE DIAGNOSTIC AND THERAPEUTIC STRATEGIES Edited by Suzanne De La Monte The Clinical Spectrum of Alzheimer’s Disease – The Charge Toward Comprehensive Diagnostic and Therapeutic Strategies Edited by Suzanne De La Monte Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2011 InTech All chapters are Open Access articles distributed under the Creative Commons Non Commercial Share Alike Attribution 3.0 license, which permits to copy, distribute, transmit, and adapt the work in any medium, so long as the original work is properly cited After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work Any republication, referencing or personal use of the work must explicitly identify the original source Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher No responsibility is accepted for the accuracy of information contained in the published articles The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book Publishing Process Manager Petra Zobic Technical Editor Teodora Smiljanic Cover Designer Jan Hyrat Image Copyright John Wollwerth, 2010 Used under license from Shutterstock.com First published August, 2011 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org The Clinical Spectrum of Alzheimer’s Disease – The Charge Toward Comprehensive Diagnostic and Therapeutic Strategies, Edited by Suzanne De La Monte p cm ISBN 978-953-307-993-6 free online editions of InTech Books and Journals can be found at www.intechopen.com Contents Preface IX Part Overview: Clinical, Epidemiological, and Genetic Factors Chapter Risk Factors for Disease Progression in Alzheimer's Disease Schmidt C, Wolff M, Shalash A and Zerr I Chapter Alzheimer’s Disease Genomics and Clinical Applications 21 Tih-Shih Lee and Mei Sian Chong Chapter Addressing Risk Factors for Neurocognitive Decline and Alzheimer’s Disease Among African Americans in the Era of Health Disparities 43 David L Mount, Maria Isabel Rego, Alethea Amponsah, Annette Herron, Darin Johnson, Mario Sims, DeMarc Hickson and Sylvia A Flack Part Non-Standard Features of Alzheimer's 61 Chapter Focal Cortical Presentations Genetically Proven Alzheimer Disease 63 Naeije G, Van den Berge Delphine, Vokaer M, Fery P, Vilain C, Abramowicz M, Van den Broeck M, Van Broeckhoven C and Bier JC Chapter Spatial Navigation Impairment in Healthy Aging and Alzheimer’s Disease 75 Kamil Vlček Chapter Visual Cognition in Alzheimer’s Disease and Its Functional Implications 101 Philip C Ko and Brandon A Ally Chapter Olfactory Dysfunctions in Alzheimer’s Disease 127 Iuliana Nicola-Antoniu VI Contents Part Neuroimaging in the Spotlight 145 Chapter Currently Available Neuroimaging Approaches in Alzheimer Disease (AD) Early Diagnosis 147 Laura Ortiz-Terán, Juan MR Santos, María de las Nieves Cabrera Martín and Tomás Ortiz Alonso Chapter The Clinical Use of SPECT and PET Molecular Imaging in Alzheimer’s Disease 181 Varvara Valotassiou, Nikolaos Sifakis, John Papatriantafyllou, George Angelidis and Panagiotis Georgoulias Part Biomarkers: Steps Toward Rapid Non-Invasive Tests Chapter 10 Cerebrospinal Fluid Based Diagnosis in Alzheimer’s Disease 207 Inga Zerr, Lisa Kaerst, Joanna Gawinecka and Daniela Varges Chapter 11 Alzheimer’s Diseases: Towards Biomarkers for an Early Diagnosis Benaïssa Elmoualij, Ingrid Dupiereux, Jérémie Seguin, Isabelle Quadrio, Willy Zorzi, Armand Perret-Liaudet and Ernst Heinen 221 Chapter 12 Phospo-PKCs in Abeta1-42-Specific Human T Cells from Alzheimer’s Disease Patients 243 Lanuti Paola, Marchisio Marco, Pierdomenico Laura and Miscia Sebastiano Chapter 13 The Predictive Role of Hyposmia in Alzheimer's Disease 259 Alessandra B Fioretti, Marco Fusetti and Alberto Eibenstein Chapter 14 Retinal Nerve Fibre Layer Thinning in Alzheimer Disease 279 Panitha Jindahra and Gordon T Plant Part Chapter 15 Potential Mechanisms of Neurodegeneration 295 Modulation of Signal Transduction Pathways in Senescence-Accelerated Mice P8 Strain: A Useful Tool for Alzheimer’s Disease Research José Luis Albasanz, Carlos Alberto Castillo, Marta Barrachina, Isidre Ferrer and Mairena Martín 297 205 Contents Chapter 16 Valosin-Containing Protein (VCP) Disease and Familial Alzheimer’s Disease: Contrasts and Overlaps 331 CD Smith, M Badadani, A Nalbandian, E Dec, J Vesa, S Donkervoort, B Martin, GD Watts, V Caiozzo and V Kimonis Chapter 17 Neural Basis of Hyposmia in Alzheimer’s Disease 347 Daniel Saiz-Sánchez, Carlos de la Rosa-Prieto, Isabel Úbeda-Bón and Alino Martínez-Marcos VII Preface The Clinical Spectrum of Alzheimer’s Disease: The Charge Toward Comprehensive Diagnostic and Therapeutic Strategies Alzheimer’s disease, the most common cause of dementia, is a degenerative disease associated with progressive destruction of the brain, resulting in behavioral/psychiatric symptoms, memory and cognitive impairments, and eventually inability to carry out normal daily activities. For over a century, Alzheimer’s disease, sometimes mispronounced “old timers’ disease” has been studied by clinicians, basic scientists, and translational investigators who work to link concepts developed by each of the other two groups. The term, ‘old timers’ is apt, because aging is by far the most dominant risk factor for the disease. Alzheimer’s disease is studied all over the world because as populations age, the prevalence rates of Alzheimer’s increase, and the personal, social, societal, economic, and emotional hardships endured over its 4 to 20 year span are staggering. Given the almost crusade‐like drive and enormous sums of money poured into just one field, and the thousands of publications resulting from decades of dedicated struggle, one cannot help but wonder, “what’s the problem?” Why are we still so deficient in our understanding of this disease? How much more time and effort are needed to finally have ways to make early, rapid, and accurate diagnoses? When will we finally have the cure, or at least some kind of treatment that can slow down the process and provide a bit more time to enjoy life in a compos mentis state? The Overview chapters in, “The Clinical Spectrum of Alzheimer’s Disease: The Charge Toward Comprehensive Diagnostic and Therapeutic Strategies”, summarize the basics and provide up‐to‐date summaries of the salient clinical, epidemiological, and genetic features of Alzheimer’s. The Chapter by Dr. Lee Tih‐Shih, in addition to reviewing genetic factors mediating Alzheimer’s, covers the use of genomics and chip arrays, approaches that will certainly be utilized in the future to identify individuals at increased risk for developing Alzheimer’s, so that preventative measures, once determined, could be implemented. The final chapter in the Overview section is unique because it highlights the shifting demographics of Alzheimer’s. Previously, Alzheimer’s was not prevalent among African American, but now is. The author links the increased rates of Alzheimer’s among African Americans to the increased rates of diabetes mellitus. Type 2 diabetes mellitus is now a very well recognized risk factor for X Preface sporadic AD, and its precursor, mild cognitive impairment. The author suggests practical measures to combat this emerging epidemic; the concepts expressed may have broader implications for the management and possibly prevention of sporadic Alzheimer’s, which accounts for at least 90 percent of all cases. The next section covers the non‐standard features of Alzheimer’s. All too often, physicians and caretakers look for only the classical features of Alzheimer’s. The four chapters included in this section discuss problems related to focal cortical degenerative effects and disorders of spatial navigation and spatial memory. Such deficits quite likely account for the increased propensity of individuals with early Alzheimer’s to get lost and become confused in new environments. The chapter by Dr. Ally Brandon discusses impairments in visual memory and cognition, which dovetails with the chapter on visual‐spatial memory impairments in Alzheimer’s. The last chapter summarizes olfactory sensory deficits in Alzheimer’s. These concepts are important because, in addition to problems with perception and memory, the primary sensory organs, eyes and nose, can and often do undergo degenerative changes, some due to aging, and others possibly as components of Alzheimer’s. The bottom line is that “non‐standard” does not mean exceptional; instead it refers to the broader spectrum of abnormalities that exist in Alzheimer’s, and that could be tapped to better understand the disease as well as improve diagnosis using non‐invasive methods. The ability to detect and monitor the progression and regional distributions of brain atrophy through neuro‐imaging approaches provides excellent tools for supporting a clinical diagnosis of Alzheimer’s, and can help distinguish the different causes of dementia. In addition, there is a growing realization that neuro‐imaging, when combined with function, such as in vivo measures of blood flow, biochemistry, and metabolism, can be powerful for improving the accuracy of early diagnosis, and potentially monitoring responses to treatment. The section, ‘Neuroimaging in the Spotlight” decodes the different approaches to neuro‐imaging currently used to evaluate people with mild cognitive impairment, Alzheimer’s disease, and other dementias. It is worthwhile knowing that as neuro‐imaging approaches become more sophisticated and refined, functional assays will become incorporated more routinely. The limitations mainly pertain to the ability to identify pathological, biochemical, and molecular markers of neurodegeneration that correlate with structural and functional neuroimaging abnormalities, and the severity of dementia. This segment of the book is particularly useful for non‐specialists and early‐stage career specialists. As mentioned, the growth and sophistication of neuroimaging are partly dependent upon understanding which molecular, biochemical, and structural abnormalities are significantly correlated with progressive neurodegeneration, and specifically, Alzheimer’s. Research in the field of Alzheimer biomarkers is robust, and the combined effects of shifting targets, paradigms, and approaches, together with the difficulties in achieving high levels of inter‐study concordance rates, make this area of investigation difficult to follow. The field is at the stage where clinicians, educators, and researchers must be knowledgeable about the state‐of‐the‐art approaches to 348 The Clinical Spectrum of Alzheimer’s Disease – The Charge Toward Comprehensive Diagnostic and Therapeutic Strategies bulbs their axons synapse with dendrites of the mitral and tufted cells which in turn project to the main olfactory cortex in the basal forebrain The human olfactory system constitutes complex circuit connections including primary and secondary cortical areas that are connected, as represented schematically in Figure Fig Schematic diagram of the human olfactory system GL, glomerular layer; Mi, mitral cell; PAC, periamygdaloid complex; Pg, periglomerular cell The progression of AD pathology has been divided into six stages according to the extent of NFT accumulation Accumulation is first detected in the entorhinal cortex and hippocampus of the limbic system; this extends into the basal forebrain including the olfactory system (Braak & Braak, 1991, Price et al., 1991, Van Hoesen et al., 1991), and from the rostral entorhinal cortex, periamygdaloid cortex, and piriform cortex, to the olfactory tubercle, anterior olfactory nucleus and olfactory bulbs (Fig 1) Tau pathology has also been described in the olfactory epithelium (Lee et al., 1993) Olfaction is affected in many psychiatric disorders in addition to AD, including Parkinson’s disease, Huntington’s disease, schizophrenia, senile dementia of Lewy body type, and depression (Atanasova et al., 2008,Kovacs, 2004) It has been widely reported over the past 25 years that olfaction is impaired in AD (Djordjevic et al., 2008, Doty et al., 1987, Mesholam et al., 1998, Murphy, 1999, Murphy et al., 1990, Serby et al., 1985, 1991), and olfaction has become a priority area in the search for biomarkers to establish an early diagnosis of AD and to facilitate early therapeutic intervention (Doty, 2003,Hampel et al., 2010,Hawkes, 2009,Wilson et al., 2009) It has been proposed that the early involvement of the entorhinal cortex and the hippocampus, regions that are tightly related to memory deficiencies (Nagy et al., 1996), could be also the cause of olfactory deficits (Wilson et al., 2007) However, other authors suggest that alternative olfactory areas, for example the posterior part of the piriform cortex, are the specific cause of olfactory deficiencies (Li et al., 2010) Nevertheless, the neural basis underlying hyposmia in the AD brain remain uncertain Neural Basis of Hyposmia in Alzheimer’s Disease 349 Materials and methods We have studied the olfactory system in 19 AD cases and age-matched controls from the Banc de Teixits Neurolịgics, Universitat de Barcelona-Hospital Clínic and the Banco de Tejidos/Fundación para Investigaciones Neurológicas, Universidad Complutense de Madrid Mean ages (± standard derivation) in AD and controls were 77.68 ± 9.01 yr and 74.57 ± 4.47 yr, respectively Tissue samples were fixed by immersion in paraformaldehyde 4% for one month at least Then, samples were cryoprotected in 30% w/v sucrose and 50µm coronal sections were obtained using a sliding freezing microtome To study the early stages of disease development we employed a double transgenic mouse model of Alzheimer disease (Appswe/Psen1Δ9) Animals at 2, 4, to months of age (n = homozygous and control female mice per group; N = 32) were collected for analysis Animals were anesthetized with a mixture of ketamine hydrochloride (Ketolar, Parke-Davis, Madrid, Spain, 1.5 ml/kg, 75 mg/kg) and xylazine (Xilagesic, Calier, Barcelona, Spain, 0.5 ml/kg, 10 mg/kg) Mice were transcardially perfused with saline solution followed by 4% w/v paraformaldehyde fixative (phosphate buffered; 0.1 M, ph 7.2) Brains were removed from skulls and cryoprotected in 30% w/v sucrose, and sectioned (50 µm) in the frontal plane (brains) or in the sagittal plane (olfactory bulbs) using a sliding freezing microtome In order to delimit areas of interest sections were stained by Nissl technique (Fig 2A) Primary antibodies used for immunodetection were mouse anti-tau (tau 46, 1:800, Cell Signaling Technology, Beverly, MA, USA), rabbit anti-Aβ (1:250, Cell Signaling Technology), and goat anti-somatostatin D-20 (1:1000, Santa Cruz Biotechnology, Santa Cruz, CA, USA) Secondary antibodies were either biotinylated (anti-goat IgG, 1:2000, Vector Laboratories, Burlingame, CA, USA) or fluorescent-labeled (1:200, alexas 488 donkey anti-mouse, 568 donkey anti-rabbit, and 350 donkey anti-goat; Molecular Probes, Invitrogen, Carlsbad, CA, USA) For quantification, somatostatin-positive cells were charted with an X-Y recording system (AccuStage, Minnesota Datametrics, MN, USA) Colocalization levels were measured by confocal microscopy using LSM 710 Zeiss confocal microscope (Carl Zeiss MicroImaging, Barcelona, Spain) Intensities of each fluorochrome were analyzed using the profile tool of the ZEN software (Zeiss) One-way ANOVA followed by post hoc Bonferroni test (p