Volume 47, Number 4, 2015

Pages 793-813

Francesco Panza*, Davide Seripa, Vincenzo Solfrizzi*, Rosanna Tortelli, Antonio Greco, Alberto Pilotto, Giancarlo Logroscino *These authors contributed equally to this work.
Targeting Cognitive Frailty: Clinical and Neurobiological Roadmap for a Single Complex Phenotype
Abstract: Late-life cognitive disorders may be prevented by influencing age-related conditions such as frailty, characterized by decreased resistance to stressors and increased risk for adverse health outcomes. In the present review article, we examined clinical and epidemiological studies investigating the possible role of different frailty models in modulating the risk of Alzheimer’s disease (AD), dementia, vascular dementia (VaD), mild cognitive impairment (MCI), and late-life cognitive impairment/decline that have been published over the past 3 years. Both deficit accumulation and physical frailty models were associated with late-life cognitive impairment/decline, incident dementia, AD, MCI, VaD, non-AD dementias, and AD pathology, proposing cognitive frailty as a new clinical construct with coexisting physical frailty and cognitive impairment in nondemented older subjects. Two subtypes of this new clinical condition have been recently proposed: “potentially reversible” cognitive frailty and “reversible” cognitive frailty. The physical factors should be physical prefrailty and frailty, while the cognitive impairment of potentially reversible cognitive frailty should be MCI (Clinical Dementia rating Scale = 0.5), while the cognitive impairment of reversible cognitive frailty should be pre-MCI Subjective Cognitive Decline (SCD), as recently proposed by the SCD Initiative Working Group. The mechanisms underlying the cognitive-frailty link are multifactorial and vascular, inflammatory, nutritional, and metabolic influences may be of major relevance. Considering both physical frailty and cognition as a single complex phenotype may be crucial in the prevention of dementia and its subtypes with secondary preventive trials on cognitive frail older subjects.

Pages 815-843

Avijit Banik*, Richard E Brown*, James Bamburg, Debomoy K. Lahiri, Dheeraj Khurana, Robert P. Friedland, Wei Chen, Ying Ding, Amritpal Mudher, Ante L Padjen, Elizabeta Mukaetova-Ladinska, Masafumi Ihara, Sudhir Srivastava, M V Padma Srivastava, Colin L Masters, Raj N Kalaria, Akshay Anand *These authors contributed equally to this work.
Translation of Pre-Clinical Studies into Successful Clinical Trials for Alzheimer’s Disease: What are the Roadblocks and How Can They Be Overcome?
Abstract:Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer’s disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.

Pages 845-855

Filipa Novais, Sergio Starkstein (Handling Associate Editor: Gwenn Smith)
Phenomenology of Depression in Alzheimer’s Disease
Abstract: Depression is among the most frequent psychiatric comorbid conditions in dementia. There is no strong consensus as to what criteria should be used to diagnose depression in AD. This is at least partially explained by the overlap between symptoms of depression and symptoms of AD. Recent studies using latent class analysis provided clarification to this diagnostic dilemma. All nine DSM-IV symptoms of major depression were found to characterize a class with a high chance (96%) of having a clinical diagnosis of major depression, and symptoms of anxiety were also frequent. Other psychiatric symptoms may also be included under the construct of depression in AD, since both apathy and anxiety are among the most frequent comorbid conditions for major depression in AD. Subtypes of depression should also be validated in this condition. For instance, increased awareness of cognitive and functional deficits is significantly associated with dysthymia but not with major depression, suggesting that different depressive syndromes in AD may have different etiology.

Pages 857-868

Francesca Pistollato, Sarah E. Cavanaugh, P. Charukeshi Chandrasekera
A Human-Based Integrated Framework for Alzheimer’s Disease Research
Abstract: Animal models of Alzheimer’s disease (AD) have been extensively utilized for decades in an effort to elucidate the pathophysiological mechanisms of this disease and to test novel therapeutic approaches. However, research success has not effectively translated into therapeutic success for human patients. This translational failure is partially due to the overuse of animal models that cannot accurately recapitulate human AD etiopathogenesis or drug responses and the inadequate use of human-relevant research methods. Here, we propose how to mitigate this translational barrier by employing human-based methods to elucidate disease processes occurring at multiple levels of complexity, accounting for gene and protein expression and the impact of disease at the cellular, tissue/organ, individual, and population levels. In particular, novel human-based cellular and computational models, together with epidemiological and clinical studies, represent the ideal tools to facilitate human-relevant data acquisition, in the effort to better elucidate AD pathogenesis in a human-based setting and design more effective treatments and preventive strategies. Our analysis indicates that a paradigm shift toward human-based, rather than animal-based research is required in the face of the ever-increasing prevalence of AD in the 21st century.

Pages 869-872

Pravat K. Mandal, Sumiti Saharan, Sarah A. Khan, Mithun James
Apps for Dementia Screening: A Cost-Effective and Portable Solution

Pages 873-876
Short Communication

Ruth Alonso, Diana Pisa, Alberto Rábano, Izaskun Rodal, Luis Carrasco
Cerebrospinal Fluid from Alzheimer’s Disease Patients Contains Fungal Proteins and DNA
Abstract: The identification of biomarkers for Alzheimer’s disease is important for patient management and to assess the effectiveness of clinical intervention. Cerebrospinal fluid (CSF) biomarkers constitute a powerful tool for diagnosis and monitoring disease progression. We have analyzed the presence of fungal proteins and DNA in CSF from AD patients. Our findings reveal that fungal proteins can be detected in CSF with different anti-fungal antibodies using a slot-blot assay. Additionally, amplification of fungal DNA by PCR followed by sequencing distinguished several fungal species. The possibility that these fungal macromolecules could represent AD biomarkers is discussed.

Pages 877-881
Short Communication

Marcella Catania, Giuseppe Di Fedea Elisa Tonoli, Luisa Benussi, Claudio Pasquali, Giorgio Giaccone, Emanuela Maderna, Roberta Ghidoni, Fabrizio Tagliavini
Mirror Image of the Amyloid-β Species in Cerebrospinal Fluid and Cerebral Amyloid in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) accumulation in brain that is paralleled by Aβ1-42 reduction in cerebrospinal fluid (CSF). We analyzed the pattern of Aβ peptides, including the N- and C-terminal truncated fragments, in brain and CSF from two familial and one sporadic AD cases. We found that (i) each patient is characterized by a distinct Aβ profile in CSF and brain deposits and (ii) the CSF Aβ pattern mirrors the Aβ profile of cerebral amyloid. These results suggest the existence of different molecular AD subtypes which can be recognized by CSF analysis, enabling patient stratification.

Pages 883-887
Ge Li*, Kangping Xiong*, Ane Korff, Catherine Pan, Joseph F. Quinn, Douglas R. Galasko, Chunfeng Liu, Thomas J. Montine, Elaine R. Peskind, Jing Zhang *These authors contributed equally to this work.
Increased CSF E-Selectin in Clinical Alzheimer’s Disease without Altered CSF Aβ42 and Tau
Abstract: Clinically diagnosed Alzheimer’s disease (AD) is pathologically heterogeneous. In this multicenter cohort of 215 clinically diagnosed AD patients and 249 controls, E-selectin and vascular cell adhesion molecule 1 (VACM-1) were measured along with amyloid-β peptide 1-42 (Aβ42) and tau. We discovered that E-selectin, a biomarker of endothelial function/vascular injury, was inversely correlated with cerebrospinal fluid (CSF) tau/Aβ42 ratio and significantly elevated in clinical AD patients without the typical AD CSF biomarker signature (i.e., low tau/Aβ42 ratio) compared to those with the signature. These findings suggest that E-selectin may be an objective biomarker related to vascular mechanisms contributing to dementia.

Pages 889-899
Vincenzo Solfrizzi*, Francesco Panza*, Bruno P. Imbimbo, Alessia D’Introno, Lucia Galluzzo, Claudia Gandin, Giovanni Misciagna, Vito Guerra, Alberto Osella, Marzia Baldereschi, Antonio Di Carlo, Domenico Inzitari, Davide Seripa, Alberto Pilotto, Carlo Sabbà, Giancarlo Logroscino, Emanuele Scafato, for the Italian Longitudinal Study on Aging Working Group (Handling Associate Editor: Patrick Kehoe) *These authors contributed equally to this work.
Coffee Consumption Habits and the Risk of Mild Cognitive Impairment: The Italian Longitudinal Study on Aging
Abstract: Coffee, tea, or caffeine consumption may be protective against cognitive impairment and dementia. We estimated the association between change or constant habits in coffee consumption and the incidence of mild cognitive impairment (MCI). We evaluated 1,445 individuals recruited from 5,632 subjects, aged 65-84 year old, from the Italian Longitudinal Study on Aging, a population-based sample from eight Italian municipalities with a 3.5-year median follow-up. Cognitively normal older individuals who habitually consumed moderate amount of coffee (from 1 to 2 cups of coffee/day) had a lower rate of the incidence of MCI than those who never or rarely consumed coffee [1 cup/day: hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.211 to 1.02 or 1-2 cups/day: HR: 0.31 95% CI: 0.13 to 0.75]. For cognitively normal older subjects who changed their coffee consumption habits, those increasing coffee consumption (> 1 cup of coffee/day) had higher rate of the incidence of MCI compared to those with constant habits (up to -/+ 1 cup of coffee/day) (HR: 1.80, 95% CI: 1.11 to 2.92) or those with reduced consumption ( 2 cups of coffee/day) and the incidence of MCI in comparison with those who never or rarely consumed coffee (HR: 0.26, 95% CI: 0.03 to 2.11). In conclusion, cognitively normal older individuals who increased their coffee consumption had a higher rate of developing MCI, while a constant in time moderate coffee consumption was associated to a reduced rate of the incidence of MCI.

Pages 901-913
Simon Cloutier, Howard Chertkow, Marie-Jeanne Kergoat, Serge Gauthier, Sylvie Belleville (Handling Associate Editor: Mark Bondi)
Patterns of Cognitive Decline Prior to Dementia in Persons with Mild Cognitive Impairment
Abstract: Only a limited number of studies have investigated the decline of discrete cognitive domains as individuals progress from mild cognitive impairment (MCI) to dementia. Thus, the goal of this longitudinal study was to evaluate the cognitive changes underway during the years preceding a diagnosis of probable Alzheimer’s disease (AD), and to compare these changes to those found in MCI patients who do not progress to dementia. Participants were compared as a function of whether they later converted to AD (n=47) or not (n=74). Cognitive change was assessed prior to the conversion year, using that year as a starting point. A combination of polynomial regression analyses and mixed ANOVAs assessed 1) the trajectory of cognitive decline for each domain and 2) the differences between non-progressors and those who had converted to AD. The different cognitive domains demonstrated very different patterns of decline in the group of MCI progressors. A quadratic function, i.e., many years of stable performance followed by a rapid decline just prior to diagnosis, was observed for delayed recall, working memory, and spatial memory. In contrast, a gradual linear decline was observed for immediate recall, executive function, and visuo-spatial abilities. Finally, language in progressors was impaired on all time periods relative to non-progressors, but there was no further change between the first assessments and conversion to AD. Individuals with MCI who progress to AD show abnormal cognition at least two years prior to their dementia diagnosis. The pattern of symptom change observed appears to depend upon the cognitive domain. In contrast and, apart from verbal memory, the non-progressors present a performance similar to that of healthy older adults.

Pages 915-926
Yongyao Fu*, Deming Zhao*, Bo Pan, Jihong Wang, Yongyong Cui, Fushan Shi, Chunyu Wang, Xiaoming Yin, Xiangmei Zhou, Lifeng Yang *These authors contributed equally to this work.
Proteomic Analysis of Protein Expression Throughout Disease Progression in a Mouse Model of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia. Mice in the transgenic AβPPswe/PS1dE9 mouse line express a chimeric mouse/human amyloid-β protein precursor (Mo/HuAβPP695swe) and mutant human presenilin 1 (PS1-dE9) associated with early-onset AD. Knowing the protein expression in these mice may offer better understanding of the pathological changes in AD. In this study, we used two-dimensional gel electrophoresis combined with mass spectrometry techniques to compare protein expression in AβPPswe/PS1dE9 mice with age-matched wild-type mice throughout the disease progression. We identified 15 proteins that were significantly different between the AβPPswe/PS1dE9 mice and age-matched controls and also changed with disease development. Among those, the expression levels of the following proteins in AβPPswe/PS1dE9 mice were at least 1.5 times higher than those in normal mice: DCC-interacting protein 13-beta, serum albumin, creatine kinase B-type, heat shock 70 kDa protein 1A, T-complex protein 1 subunit beta, adenylate kinase isoenzyme 1, pyruvate dehydrogenase E1 component subunit beta mitochondrial, and V-type proton ATPase catalytic subunit A. Levels of the following proteins in AβPPswe/PS1dE9 mice were at least 1.5 times lower than those in normal mice: dihydropyrimidinase-related protein 2, actin cytoplasmic 2, isoform 1 of V-type proton ATPase catalytic subunit, tubulin alpha-1C chain, F-actin-capping protein subunit alpha-2, ubiquitin carboxyl-terminal hydrolase isozyme L1, and actin cytoplasmic 1. These proteins are involved in regulating various cellular functions, including cytoskeletal structure, energy metabolism, synaptic components, and protein degradation. These findings indicate altered protein expression in the pathogenesis of AD and illuminate novel therapeutic avenues for treatment in AD.

Pages 927-937
Xin Wang, Jin Cui, Wei Li, Xianglu Zeng, Jian Zhao, Gang Pei
γ-Secretase Modulators and Inhibitors Induce Different Conformational Changes of Presenilin 1 Revealed by FLIM and FRETAbstract: Elucidation of γ-secretase structure and dynamic conformational changes is of importance to drug discovery targeting this enzyme. Electron microscopy analyses provided important structural information, but the dynamic changes of γ-secretase in cells need to be explored further. We found that PS1 internal fluorescence resonance energy transfer (FRET) probes can incorporate into γ-secretase complex and possess secretase activity. Our results from fluorescence lifetime image microscopy (FLIM) and acceptor photobleaching FRET show different PS1 internal FRET when PS1 fluorescent probes expressed alone or with other secretase subunits Aph1aL, Nicastrin, and Pen2, indicating that PS1 internal FRET could be applied for probing conformational change of γ-secretase complex. Further, we accessed whether γ-secretase activity interfering compounds induced different conformational changes of PS1. Our results show that both γ-secretase modulators and inhibitors affect PS1 internal FRET but in different manners. These results demonstrate that FLIM and acceptor photobleaching FRET could be applied to monitor different PS1 conformational changes in γ-secretase.

Pages 939-954
Stefan Klöppel, Jessica Peter, Anna Ludl, Anne Pilatus, Sabrina Maier, Irina Mader, Bernhard Heimbach, Lars Frings, Karl Egger, Juergen Dukart, Matthias L. Schroeter, Robert Perneczky, Peter Häussermann, Werner Vach, Horst Urbach, Stefan Teipel, Michael Hüll, Ahmed Abdulkadir, for the Alzheimer's Disease Neuroimaging Initiative
Applying Automated MR-Based Diagnostic Methods to the Memory Clinic: A Prospective Study
Abstract: Several studies have demonstrated that fully automated pattern recognition methods applied to structural magnetic resonance imaging (MRI) aid in the diagnosis of dementia, but these conclusions are based on highly preselected samples that significantly differ from that seen in a dementia clinic. At a single dementia clinic, we evaluated the ability of a linear support vector machine trained with completely unrelated data to differentiate between Alzheimer’s disease (AD), frontotemporal dementia (FTD), Lewy body dementia, and healthy aging based on 3D-T1 weighted MRI data sets. Furthermore, we predicted progression to AD in subjects with mild cognitive impairment (MCI) at baseline and automatically quantified white matter hyperintensities from FLAIR-images. Separating additionally recruited healthy elderly from those with dementia was accurate with an area under the curve (AUC) of 0.98. Multi-class separation of 138 patients with either AD or FTD from other included groups was good on the training set (AUC>0.9) but substantially less accurate (AUC=0.76 for AD and 0.78 for FTD) on data from the local clinic. Longitudinal data from 28 cases with MCI at baseline and appropriate follow-up data were available. The computer tool discriminated progressive from stable MCI with AUC=0.73, compared to AUC=0.80 for the training set. A relatively low accuracy by clinicians (AUC=0.81) illustrates the difficulties of predicting conversion in this heterogeneous cohort. This first application of a MRI-based pattern recognition method to a routine sample demonstrates feasibility, but also illustrates that automated multi-class differential diagnoses have to be the focus of future methodological developments and application studies.

Pages 955-964
Yakeel T. Quiroz , Kim Celone Willment, Gabriel Castrillon, Martha Muniz, Francisco Lopera, Andrew Budson, Chantal E. Stern (Handling Associate Editor: Natalie Ryan)
Successful Scene Encoding in Presymptomatic Early-Onset Alzheimer’s Disease
Background: Brain regions critical to episodic memory are altered during the preclinical stages of Alzheimer’s disease (AD). However, reliable means of identifying cognitively-normal individuals at higher risk to develop AD have not been established. Objective: To examine whether functional MRI can detect early functional changes associated with scene encoding in a group of presymptomatic presenilin-1 (PSEN1) E280A mutation carriers. Methods: Participants were 39 young, cognitively-normal individuals from an autosomal dominant early-onset AD kindred, located in Antioquia, Colombia. Participants performed a functional MRI scene encoding task and a post-scan subsequent memory test. esults: PSEN1 mutation carriers exhibited hyperactivation within medial temporal lobe regions during successful scene encoding (hippocampal formation, parahippocampal gyrus) compared to age-matched non-carriers. Conclusion: Hyperactivation in medial temporal lobe regions during scene encoding is seen in individuals genetically-determined to develop AD years before their clinical onset. Our findings will guide future research with the ultimate goal of using functional neuroimaging in the early detection of preclinical AD.

Pages 965-975
Charles B. Malpas, Michael M. Saling, Dennis Velakoulis, Patricia Desmond, Terence J. O’Brien, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Carlo Abbate)
Tau and Amyloid-β Cerebrospinal Fluid Biomarkers have Differential Relationships with Cognition in Mild Cognitive Impairment
Abstract: Alzheimer’s disease (AD) is characterized by two primary pathologies: tau-related neurofibrillary tangles and the extracellular accumulation of amyloid-β (Aβ). The development of these pathologies is topologically distinct early in the disease, with Aβ beginning to accumulate as a diffuse, neocortical pathology, while tau-related pathology begins to form in mesial temporal regions. This study investigated the hypothesis that, by virtue of this distinction, there exist preferential associations between the primary pathologies and aspects of the cognitive phenotype. We investigated the relationship between cerebrospinal fluid (CSF) biomarkers for tau and Aβ pathologies with neurocognitive measures in 191 patients with mild cognitive impairment (MCI). Participants completed cognitive tests of new learning, information processing speed, and working memory. Separate regression models were computed and then followed up with mediation analyses to examine the predictive status of CSF biomarkers. The effect of Aβ on learning was mediated by phospho-tau (p = 0.008). In contrast, Aβ had a direct effect on information processing speed that was not mediated by phospho-tau (p = 0.59). No predictors were significant for working memory. This study provided evidence for a differential relationship of Aβ and phospho-tau pathologies on the neurocognitive phenotype of MCI. This supports the proposition that these primary AD pathologies maximally affect different aspects of cognition, and has potential implications for cognitive assessments and the use of biomarkers in disease-modifying therapeutic trials.

Pages 977-984
Flavio Dell’Acqua*, Wasim Khan*, Natalie Gottlieb, Vincent Giampietro, Cedric Ginestet, David Bouls, Steven Newhouse, Richard Dobson, Tobias Banaschewski, Gareth J. Barker, Arun L.W. Bokde, Christian Büchel, Patricia Conrod, Herta Flor, Vincent Frouin, Hugh Garavan, Penny Gowland, Anreas Heinz, Hervé Lemaître, Frauke Nees, Tomas Paus, Zdenka Pausova, Marcella Rietschel, Michael N. Smolka, Andreas Ströhle, Jean Gallinat, Eric Westman, Gunther Schumann, Simon Lovestone, Andrew Simmons and the IMAGEN consortium (Handling Associate Editor: Maheen Adamson) *These authors contributed equally to this work.
Tract Based Spatial Statistic Reveals No Differences in White Matter Microstructural Organization between Carriers and Non-Carriers of the APOE ε4 and ε2 Alleles in Young Healthy Adolescents
Abstract: The apolipoprotein E (APOE) ε4 allele is the best established genetic risk factor for Alzheimer’s disease (AD) and has been previously associated with alterations in structural gray matter and changes in functional brain activity in healthy middle-aged individuals and older non-demented subjects. In order to determine the neural mechanism by which APOE polymorphisms affect white matter (WM) structure, we investigated the diffusion characteristics of WM tracts in carriers and non-carriers of the APOE ε4 and ε2 alleles using an unbiased whole brain analysis technique (Tract Based Spatial Statistics) in a healthy young adolescent (14 years) cohort. A large sample of healthy young adolescents (n=575) were selected from the European neuroimaging-genetics IMAGEN study with available APOE status and accompanying diffusion imaging data. MR Diffusion data was acquired on 3T systems using 32 diffusion-weighted (DW) directions and 4 non-DW volumes (b-value = 1,300 s/mm2 and isotropic resolution of 2.4 x 2.4 x 2.4 mm). No significant differences in WM structure were found in diffusion indices between carriers and non-carriers of the APOE ε4 and ε2 alleles, and dose-dependent effects of these variants were not established, suggesting that differences in WM structure are not modulated by the APOE polymorphism. In conclusion, our results suggest that microstructural properties of WM structure are not associated with the APOE ε4 and ε2 alleles in young adolescence, suggesting that the neural effects of these variants are not evident in 14-year-olds and may only develop later in life.

Pages 985-993
Mario F. Mendez, Pongsatorn Paholpak, Andrew Lin, Jeannie Y. Zhang, Edmond Teng (Handling Associate Editor: Tania Alves)
Prevalence of Traumatic Brain Injury in Early Versus Late-Onset Alzheimer’s Disease
Abstract: Background: Traumatic brain injury (TBI) is the most established environmental risk factor for Alzheimer’s disease (AD), but it is unclear if TBI is specifically associated with early-onset AD (EOAD). Objective: To evaluate the relationship between TBI and EOAD (<65 years). Methods: We identified 1,449 EOAD, 4,337 late-onset AD (LOAD), and corresponding EOAD-matched and LOAD-matched normal controls (NC) in the National Alzheimer’s Coordinating Center Uniform (NACC) database and compared the prevalence of any history of TBI as well as measures of cognition, function, behavior, and neuropathology. For validation, we determined TBI prevalence among 115 well-characterized clinic patients with EOAD. Results: Part A: The prevalence of any TBI in the NACC-database EOAD participants (13.3%) was comparable to that observed in the clinic EOAD patients (13.9%) but significantly higher than in the NACC-database LOAD participants (7.7%; p<0.0001) and trended to higher compared to EOAD-matched NC (11.1%; logistic regression p=0.053). Part B: When we compared EOAD patients with documented non-acute and non-residually impairing TBI to EOAD without a documented history of prior TBI, those with TBI had significantly more disinhibition. Part C: Autopsies did not reveal differences in AD neuropathology based on a history of TBI. Conclusions: These findings suggest, but do not establish, that TBI is a specific risk factor for EOAD and may lead to disinhibition, a feature that often results from the frontal effects of head injury. This study recommends further research on the effects of TBI in EOAD in larger numbers of participants.

Pages 995-1007
Marina Weiler, Federica Agosta, Elisa Canu, Massimiliano Copetti, Giuseppe Magnani, Alessandra Marcone, Elisabetta Pagani, Marcio Luiz Figueredo Balthazar, Giancarlo Comi, Andrea Falini, Massimo Filippi
Following the Spreading of Brain Structural Changes in Alzheimer’s Disease: A Longitudinal, Multimodal MRI Study
Abstract: Background. Longitudinal MRI studies in Alzheimer’s disease (AD) are one of the most reliable way to track brain changes along the course of the disease. Objective. To investigate the evolution of grey matter (GM) atrophy and white matter (WM) damage in AD patients, and to assess the relationships of MRI changes with baseline clinical and cognitive variables and their evolution over time. Methods. Clinical, neuropsychological, and MRI assessments (T1-weighted and diffusion tensor [DT]-MRI) were obtained from 14 patients with AD at baseline and after a 16±3 month period. Lumbar puncture was obtained at study entry. At baseline, AD patients were compared to 37 controls. GM atrophy progression was assessed with tensor-based morphometry and GM volumes of interest, and WM damage progression using tract-based spatial statistics and tractography. Results. At baseline, patients showed cortical atrophy in the medial temporal and parietal regions and a widespread pattern of WM damage involving the corpus callosum, cingulum, and temporo-occipital, parietal, and frontal WM tracts. During follow up, AD patients showed total GM atrophy, while total WM volume did not change. GM tissue loss was found in frontal, temporal, and parietal regions. In addition, AD patients showed a progression of WM microstructural damage to the corpus callosum, cingulum, fronto-parietal and temporo-occipital connections bilaterally. Patients with higher baseline cerebrospinal fluid total tau showed greater WM integrity loss at follow up. GM and WM changes over time did not correlate each other nor with cognitive evolution. Conclusion. In AD, GM atrophy and WM tract damage are likely to progress, at least partially, independently. This study suggests that a multimodal imaging approach, which includes both T1-weighted and DT MR imaging, may provide additional markers to monitor disease progression.

Pages 1009-1019
Carey E. Gleason, Barbara L. Fischer, N. Maritza Dowling, Kenneth D.R. Setchell, Craig S. Atwood, Cynthia M. Carlsson, Sanjay Asthana
Cognitive Effects of Soy Isoflavones in Patients with Alzheimer’s Disease
Abstract: Background: In a previous trial, treatment with soy isoflavones was associated with improved nonverbal memory, construction, verbal fluency, and speeded dexterity compared to treatment with placebo in cognitively healthy older adults. Objective: The current trial aimed to examine the potential cognitive benefits of soy isoflavones in patients with Alzheimer's disease. Methods: Sixty-five men and women over the age of 60 were treated with 100 mg/day soy isoflavones, or matching placebo capsules for six months. APOE genotype was determined for all participants. Cognitive outcomes and plasma isoflavone levels were measured at baseline, and at two additional time points: three and six months after baseline. Results: Of the sixty-five participants enrolled, thirty-four (52.3%) were women, and 31 (47.7%) were APOE4 positive. Average age was 76.3 (SD=7.2) years. Fifty-nine (90.8%) subjects completed all study visits. Plasma isoflavone levels increased in subjects treated with soy isoflavones compared to baseline and to placebo, although intersubject variability in plasma levels was large. No significant differences in treatment effects for cognition emerged between treatment groups or genders. Exploratory analyses of associations between changes in cognition and plasma isoflavone levels revealed an association between equol levels, and speeded dexterity and verbal fluency. Conclusions: Six months of 100 mg/day treatment with soy isoflavones did not benefit cognition in older men and women with Alzheimer’s disease. However, our results suggest the need to examine the role of isoflavone metabolism, i.e., the ability to effectively metabolize soy isoflavones by converting daidzen to equol when attempting to fully clarify the cognitive effects of isoflavones.

Pages 1021-1033
Kai Liu*, Jeremy E. Chojnacki*, Emily E. Wade, John M. Saathoff, Edward J. Lesnefsky, Qun Chen, Shijun Zhang (Handling Associate Editor: Weiming Xia) *These authors contributed equally to this work.
Bivalent Compound 17MN Exerts Neuroprotection through Interaction at Multiple Sites in a Cellular Model of Alzheimer’s Disease
Abstract: Multiple pathogenic factors have been suggested to play a role in the development of Alzheimer’s disease (AD). The multifactorial nature of AD also suggests the potential use of compounds with polypharmacology as effective disease-modifying agents. Recently, we have developed a bivalent strategy to include cell membrane anchorage into the molecular design. Our results demonstrated that the bivalent compounds exhibited multifunctional properties and potent neuroprotection in a cellular AD model. Herein, we report the mechanistic exploration of one of the representative bivalent compounds, 17MN, in MC65 cells. Our results established that MC65 cells die through a necroptotic mechanism upon the removal of tetracycline (TC). Furthermore, we have shown that mitochondrial membrane potential and cytosolic Ca2+ levels are increased upon removal of TC. Our bivalent compound 17MN can reverse such changes and protect MC65 cells from TC removal induced cytotoxicity. The results also suggest that 17MN may function between the Aβ species and RIPK1 in producing its neuroprotection. Colocalization studies employing a fluorescent analog of 17MN and confocal microscopy demonstrated the interactions of 17MN with both mitochondria and endoplasmic reticulum, thus suggesting that 17MN exerts its neuroprotection via a multiple-site mechanism in MC65 cells. Collectively, these results strongly support our original design rationale of bivalent compounds and encourage further optimization of this bivalent strategy to develop more potent analogs as novel disease-modifying agents for AD.

Pages 1035-1046
Wei Feng*, Jennifer S. Yokoyama*, Shunying Yu, You Chen, Yan Cheng, Luke W. Bonham, Dongxiang Wang, Yuan Shen, Wenyuan Wu, Chunbo Li (Handling Associate Editor: Shea Andrews) *These authors contributed equally to this work.
APOE Genotype Affects Cognitive Training Response in Healthy Shanghai Community-Dwelling Elderly Individuals
Abstract: Background: Cognitive training may contribute to the ability to maintain cognitive function in healthy elderly adults. Whether genotype modifies training effects remains unknown.Objective: Assess influence of APOE on cognitive function over time in community-dwelling elderly adults participating in multi-domain cognitive training. Methods: Healthy individuals ≥70 years of age were screened from one urban community in Shanghai. 145 healthy Chinese older adults met inclusion criteria and were assigned to intervention (n=88) or control (n=57) groups. Multi-domain cognitive training involved 24 sessions of different content taking place over 12 weeks. Neuropsychological testing was administered at baseline, immediately after training, six months and twelve months post-intervention; composite measures of cognitive function were identified via factor analysis. Results: Three factors explained the majority of variance in function (verbal memory, processing speed, executive function). The intervention attenuated 12-month declines in processing speed, regardless of APOE genotype (p=0.047). Executive function declined in APOE ε4 carriers over 12 months, regardless of intervention (p=0.056). There was a significant interaction after 12 months where intervention ε4 carriers had better processing speed than ε4 controls (p=0.003). Intervention ε2 carriers had better executive function immediately after training (p=0.02) and had better verbal memory 6-months post-intervention (p=0.04). These effects remained significant after false-discovery rate correction. Conclusion: Multi-domain cognitive training reduces declines in processing speed over time. APOE ε4 is associated with reductions in executive function over time, and training may attenuate ε4-associated declines in processing speed. APOE ε2 carriers may also benefit from training, particularly on measures of executive function and verbal memory.

Pages 1047-1056
Janusz Kocki*, Marzena Ułamek-Kozioł*, Anna Bogucka-Kocka, Sławomir Januszewski, Mirosław Jabłoński, Paulina Gil-Kulik, Judyta Brzozowska, Alicja Petniak, Wanda Furmaga-Jabłońska, Jacek Bogucki, Stanisław J. Czuczwar, Ryszard Pluta *These authors contributed equally to this work.
Dysregulation of Amyloid-β Protein Precursor, β-Secretase, Presenilin 1 and 2 Genes in the Rat Selectively Vulnerable CA1 Subfield of Hippocampus Following Transient Global Brain Ischemia
Abstract: The interaction between brain ischemia and Alzheimer’s disease (AD) has been intensively investigated recently. Nevertheless, we have not yet understood the nature and mechanisms of the ischemic episodes triggering the onset of AD and how they influence its slow progression. The assumed connection between brain ischemia and the accumulation of amyloid-β (Aβ) peptide awaits to be clearly explained. In our research, we employed a rat cardiac arrest model to study the changes in gene expression of amyloid-β protein precursor (AβPP) and its cleaving enzymes, β- and γ-secretases (including presenilins) in hippocampal CA1 sector, following transient 10-min global brain ischemia. The quantitative reverse-transcriptase PCR assay demonstrated that the expression of all above genes that contribute to Aβ peptide generation was dysregulated during 30 days in postischemic hippocampal CA1 area. It suggests that studied Aβ peptide generation-related genes can be involved in AβPP metabolism, following global brain ischemia and will be useful to identify the molecular mechanisms underpinning the relationship of ischemic brain episodes with etiology of AD and neuronal death. In conclusion, our study adds strong evidence that cerebral ischemia might be an etiological cause of AD via dysregulation of AβPP and its cleaving enzymes, β- and γ-secretases genes, and subsequently, it may increase Aβ peptide production and promote the gradual and slow development of AD neuropathology. Our data demonstrate that brain ischemia activates delayed neuronal death in hippocampus in an AβPP-dependent manner, thus defining a new and important mode of ischemic cell death.

Pages 1057-1067
Ye Zhan, Kewei Chen, Xia Wu, Daoqiang Zhang, Jiacai Zhang, Li Yao, Xiaojuan Guo, for the Alzheimer's Disease Neuroimaging Initiative (Handling Associate Editor: Claudio Babiloni)
Identification of Conversion from Normal Elderly Cognition to Alzheimer’s Disease using Multimodal Support Vector Machine
Abstract: Alzheimer’s disease (AD) is one of the most serious progressive neurodegenerative diseases among the elderly, therefore the identification of conversion to AD at the earlier stage has become a crucial issue. In this study, we applied multimodal support vector machine to identify the conversion from normal elderly cognition to mild cognitive impairment (MCI) or AD based on magnetic resonance imaging and positron emission tomography data. The participants included two independent cohorts (Training set: 121 AD patients and 120 normal controls (NC); Testing set: 20 NC converters and 20 NC non-converters) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The multimodal results showed that the accuracy, sensitivity, and specificity of the classification between NC converters and NC non-converters were 67.5%, 73.33%, and 64%, respectively. Furthermore, the classification results with feature selection increased to 70% accuracy, 75% sensitivity, and 66.67% specificity. The classification results using multimodal data are markedly superior to that using a single modality when we identified the conversion from NC to MCI or AD. The model built in this study of identifying the risk of normal elderly converting to MCI or AD will be helpful in clinical diagnosis and pathological research.

Pages 1069-1078
Maria Travassos, Isabel Santana, Inês Baldeiras, Magda Tsolaki, Olymbia Gkatzima, Sermin Genc, Görsev G. Yener, Anja Simonsen, Steen G. Hasselbalch, Elisabeth Kapaki, Mara Bourbouli, Rodrigo A. Cunha, Paula Agostinho, Kaj Blennow, Henrik Zetterberg, Vera M. Mendes, Bruno Manadas, Alexandre de Mendonça
Does Caffeine Consumption Modify Cerebrospinal Fluid Amyloid-β Levels in Patients with Alzheimer’s Disease?
Abstract: Caffeine may be protective against Alzheimer’s disease (AD) by modulating amyloid-β (Aβ) metabolic pathways. The present work aimed to study a possible association of caffeine consumption with the cerebrospinal fluid (CSF) biomarkers, particularly Aβ. The study included 88 patients with AD or mild cognitive impairment. The consumption of caffeine and theobromine was evaluated using a validated food questionnaire. Quantification of caffeine and main active metabolites was performed with liquid chromatography coupled to tandem mass spectrometry. The levels of Aβ1-42, total tau, and phosphorylated tau in the CSF were determined using sandwich ELISA methods and other Aβ species, AβX-38, AβX-40, and AβX-42, with the MSD Aβ Triplex assay. The concentration of caffeine was 0.79 ± 1.15 μg/mL in the CSF and 1.20 ± 1.88 μg/mL in the plasma. No correlation was found between caffeine consumption and Aβ42 in the CSF. However, a significant positive correlation was found between the concentrations of theobromine, both in the CSF and in the plasma, with Aβ42 in the CSF. Theobromine in the CSF was positively correlated with the levels of other xanthines in the CSF, but not in the plasma, suggesting that it may be formed by central metabolic pathways. In conclusion, caffeine consumption does not modify the levels of CSF biomarkers, and does not require to be controlled for when measuring CSF biomarkers in a clinical setting. Since theobromine is associated with a favorable Aβ profile in the CSF, the possibility that it might have a protective role in AD should be further investigated.