Volume 45, Number 1, 2015

Pages 1-14
Julia Fernández-Montoya, Mar Pérez
Cathepsin D in a Murine Model of Frontotemporal Dementia with Parkinsonism-Linked to Chromosome 17
Abstract: Tauopathies, such as Alzheimer’s disease (AD) and Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), are characterized by tau accumulation. This accumulation could result from alterations in tau degradation by either the ubiquitin-proteasome system or the autophagy–lysosomal pathway. To analyze a possible alteration of the autophagy–lysosomal pathway in transgenic mice expressing human tau with three FTDP-17 missense mutations (TauVLW mice), we studied the lysosomal enzyme Cathepsin D. The hippocampi of TauVLW mice, where the human mutant tau accumulates, showed both increased Cathepsin D and partial colocalization of Cathepsin D with human mutant tau. At the ultrastructural level, some multivesicular bodies showed human mutant tau-immunopositive vesicles. This finding could provide insights into the molecular mechanisms of tau degradation in human tauopathies.

Pages 15-25
Shogyoku Bun, Chiaki Ikejima, Jiro Kida, Atsuko Yoshimura, Adam Jon Lebowitz, Tatsuyuki Kakuma, Takashi Asada
A Combination of Supplements May Reduce the Risk of Alzheimer’s Disease in Elderly Japanese with Normal Cognition
Abstract: A number of studies have examined the effect of a single supplement against Alzheimer’s disease (AD) with conflicting results. Taking into account the complex and multifactorial nature of AD pathogenesis, multiple supplements may be more effective. Physical activity is another prospect against AD. An open-label intervention study was conducted to explore a potential protective effect of multiple supplements and physical activity. Their interaction was also examined. Participants were community-dwelling volunteers aged 65 or older as of May 2001 in a rural area of Japan. Among 918 cognitively normal participants included in the analyses, 171 took capsules daily for three years that contained n-3 polyunsaturated fatty acid, Ginkgo biloba leaf dry extracts, and lycopene. Two hundred and forty one participants joined the two-year exercise intervention that included a community center-based and a home-based exercise program. One-hundred and forty eight participated in both interventions. A standardized neuropsychological battery was administered at baseline in 2001, the first follow-up in 2004-2005, and the second in 2008-2009. The primary outcome was AD diagnosis at follow-ups. A complementary log to log model was used for survival analysis. A total of 76 participants were diagnosed with AD during follow-up periods. Higher adherence to supplementation intervention was associated with lower AD incidence in both unadjusted and adjusted models. Exercise intervention was also associated with lower AD incidence in the unadjusted model, but not in the adjusted model. We hypothesized that the combination of supplements acted in a complementary and synergistic fashion to bring significant effects against AD occurrence.

Pages 27-33
Phillip J. Hsu, Haochang Shu, Tammie Benzinger, Daniel Marcus, Tony Durbin, John C. Morris, Yvette I. Sheline
Amyloid Burden in Cognitively Normal Elderly is Associated with Preferential Hippocampal Subfield Volume Loss
Abstract: The earliest sites of brain atrophy in Alzheimer’s disease are in the medial temporal lobe, following widespread cerebral cortical amyloid deposition. We assessed 74 cognitively normal participants with clinical measurements, amyloid-β-PET imaging, MRI, and a newly developed technique for MRI-based hippocampal subfield segmentation to determine the differential association of amyloid deposition and hippocampal subfield volume. Compared to amyloid-negative participants, amyloid-positive participants had significantly smaller hippocampal tail, presubiculum, subiculum, and total hippocampal gray matter volumes. We conclude that, prior to the development of cognitive impairment, atrophy in particular hippocampal subfields occurs preferentially with amyloid-β accumulation.

Pages 35-43
Wesley Jongbloed, Kim A. Bruggink, Maartje I. Kester, Pieter-Jelle Visser, Philip Scheltens, Marinus A. Blankenstein1, Marcel M. Verbeek, Charlotte E. Teunissen, Robert Veerhuis (Handling Associate Editor: Henrietta Nielsen)
Amyloid-β Oligomers Relate to Cognitive Decline in Alzheimer’s Disease
Abstract: Background: Amyloid-β (Aβ)-oligomers are neurotoxic isoforms of Aβ and are a potential diagnostic biomarker for Alzheimer’s disease (AD). Objectives: 1) Analyze the potential of Aβ-oligomer concentrations in cerebrospinal fluid (CSF) to diagnose and predict progression to AD in a large clinical study sample. 2) Monitor Aβ-oligomer concentrations over-time, both in early and advanced stages of AD. 3) Examine the relation between Aβ-oligomer levels in CSF and cognitive functioning. Methods: 24 non-demented, 61 mild cognitive impairment (MCI), and 64 AD patients who underwent lumbar puncture and cognitive testing at baseline and follow-up were selected from the memory clinic based Amsterdam Dementia Cohort. CSF samples were analyzed for standard AD-biomarkers and Aβ-oligomer levels using a validated in-house Aβ-oligomer specific enzyme-linked immunosorbent assay. Aβ-oligomer levels were analyzed as indicators of disease progression (follow-up AD diagnosis) and cognitive decline, respectively. Results. Patient groups did not differ in Aβ-oligomer concentrations at baseline or follow-up. Baseline CSF Aβ-oligomer levels were similar in MCI patients that develop AD as in stable MCI patients. MCI and AD patients showed an annual decrease in Aβ-oligomer levels of 9.4% and 6.8%, respectively. A decrease in Aβ-oligomer levels over time was strongly associated with more severe cognitive decline in AD patients. Conclusion. Despite the limited diagnostic potential of Aβ-oligomer levels in CSF to differentiate between patient groups, and between MCI-AD and MCI-stable patients, changes in CSF Aβ-oligomer levels were related to cognitive decline. Therefore, CSF Aβ-oligomers may aid in the selection of patients with a more aggressive disease course.

Pages 45-56
Carol Yim-lui Cheung*, Yi Ting Ong*, Saima Hilal, M. Kamran Ikram, Sally Low, Yi Lin Ong, N. Venketasubramanian, Philip Yap, Dennis Seow, Christopher Li Hsian Chen +, Tien Yin Wong+ *These authors contributed equally to this work as first authors. +These authors contributed equally to the work as last authors.
Retinal Ganglion Cell Analysis Using High-Definition Optical Coherence Tomography in Patients with Mild Cognitive Impairment and Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder with emerging evidence that it is associated with retinal ganglion cell loss; however, few data exist to establish this association. Objective: To determine whether macular ganglion cell-inner plexiform layer (GC-IPL) and retinal nerve fiber layer (RNFL), as quantitatively measured by non-invasive in vivo spectral-domain optical coherence tomography (SD-OCT), are altered in patients with AD and mild cognitive impairment (MCI). Methods: Patients with AD and MCI were recruited from dementia/memory clinics, and cognitively normal controls were selected from the Singapore Epidemiology of Eye Disease program. SD-OCT (CIRRUS, software version 6.0.2, Carl Zeiss Meditec Inc, Dublin, CA) was used to measure the GC-IPL and RNFL thicknesses. Results: Compared with cognitively normal controls (n=123), patients with AD (n=100) had significantly reduced GC-IPL thicknesses in all six (superior, superonasal, inferonasal, inferior, inferotemporal, and superotemporal) sectors (mean differences from -3.42 to -4.99 µm, all p<0.05) and reduced RNFL thickness in superior quadrant (-6.04 µm, p=0.039). Patients with MCI (n=41) also had significantly reduced GC-IPL thicknesses compared with controls (mean differences from -3.62 to -5.83 µm, all p<0.05). Area under receiver operating characteristic curves of GC-IPL were generally higher than that of RNFL to discriminate AD and MCI from the controls. Conclusions: Our data strengthens the link between retinal ganglion cell neuronal and optic nerve axonal loss with AD, and suggest that assessment of macular GC-IPL can be a test to detect neuronal injury in early AD and MCI.

Pages 57-73
Illana Gozes, Adva Yeheskel, Metsada Pasmanik-Chor
Activity-Dependent Neuroprotective Protein (ADNP): A Case Study for Highly Conserved Chordata-Specific Genes Shaping the Brain and Mutated in Cancer
Abstract: The recent finding of activity-dependent neuroprotective protein (ADNP) as a protein decreased in serum of patients with Alzheimer’s disease (AD) compared to controls, alongside with the discovery of ADNP mutations in autism and coupled with the original description of cancer mutations, ignited an interest for a comparative analysis of ADNP with other AD/autism/cancer-associated genes. We strive toward a better understanding of the molecular structure of key players in psychiatric/neurodegenerative diseases including autism, schizophrenia, and AD. This article includes data mining and bioinformatics analysis on the ADNP gene and protein, in addition to other related genes, with emphasis on recent literature. ADNP is discovered here as unique to chordata with specific autism mutations different from cancer-associated mutation. Furthermore, ADNP exhibits similarities to other cancer/autism-associated genes. We suggest that key genes, which shape and maintain our brain and are prone to mutations and are by in large unique to chordata. Furthermore, these brain-controlling genes, like ADNP, are linked to cell growth and differentiation, and under different stress conditions may mutate or exhibit expression changes leading to cancer propagation. Better understanding of these genes could lead to better therapeutics.

Pages 75-88
Simon Lovestone, Mercè Boada, Bruno Dubois, Michael Hüll, Juha O. Rinne, Hans-Jürgen Huppertz, Miguel Calero, María V. Andrés, Belén Gómez-Carrillo, Teresa León, Teodoro del Ser for the ARGO investigators
A Phase II Trial of Tideglusib in Alzheimer’s Disease
Abstract: Background: The ARGO study was a phase II, double-blind, placebo controlled, four parallel arm trial of tideglusib in Alzheimer’s disease (AD). Objective: To prove the clinical efficacy of an inhibitor of glycogen synthase kinase-3 (GSK-3), in AD. Methods: Mild to moderate (Mini-Mental State Examination (MMSE) score, 14-26) AD patients on cholinesterase inhibitor and/or memantine treatment were administered tideglusib or placebo for 26 weeks. The ADAS-cog15 was the primary efficacy measure; function, cognition, behavior, and quality of life were assessed as secondary measures; cerebral atrophy in MRI and the levels of tau, amyloid-β, and BACE1 in cerebrospinal fluid (CSF) were exploratory endpoints. Results: 306 AD patients were randomized to active (1000 mg QD: n=86, 1000 mg QOD: n=90, and 500 mg QD: n=50) or placebo (n=85) in 55 sites in four European countries. There were no statistically significant differences between either active and placebo arms in the efficacy variables. However, BACE1 in CSF significantly decreased with treatment in a small subgroup of patients. Participants with mild AD in the 500 mg QD group showed significant responses on ADAS-cog15, MMSE, and word fluency. Diarrhea (14-18% in active, 11% placebo) and dose-dependent, mild to moderate, and fully reversible transaminase increase (9-16% in active, 3.5% placebo) were the most frequent adverse events. Conclusions: Short term (26 weeks) tideglusib was acceptably safe but produced no clinical benefit in this trial. However, given the non-linear dose response, especially in mildly affected patients, further dose finding studies in early disease stages and for longer duration are warranted to examine GSK-3 inhibition in AD patients.

Pages 89-95
Fiammetta Monacelli, Roberta Borghi, Sergio Cammarata, Alessio Nencioni, Alessandra Piccini, Massimo Tabaton, Patrizio Odetti
Amnestic Mild Cognitive Impairment and Conversion to Alzheimer’s Disease: Insulin Resistance and Glycoxidation as Early Biomarker Clusters
Abstract: Autopsy studies have indicated brain accumulation of amyloid-β peptides as a common pathogenetic hallmark of amnestic cognitive impairment (aMCI) and overt Alzheimer’s disease (AD). The pathogenesis of AD is still debated but recent reports have even designated AD as type III diabetes. This study aims to assess plasma levels of malondialdehyde, pentosidine, and insulin resistance in a group of aMCI patients, AD subjects, and age- and gender-matched controls, to confirm, beyond the accumulation of amyloid-β, the presence of a metabolic disorder, as a causative/contributive factor for AD. Patients were recruited and diagnosed as aMCI (n=180), AD (n=84), and age- and gender-matched controls (n=62) at three different Italian memory clinics. Plasma insulin and glucose, plasma pentosidine and malondialdehyde (MDA), HOMA-IR and QUICKI score for insulin sensitivities indexes were collected at the basal visit. Plasma MDA levels were higher in the aMCI group who converted to AD compared to controls, stable aMCI subjects, and AD subjects (p<0.01) respectively, while plasma pentosidine was higher compared to controls. The aMCI group showed a significant correlation between HOMA-IR, QUICKI, insulin, and MDA (p<0.012). aMCI might be considered the early biochemical active disease stage where glycoxidation, hyperinsulinemia, and pro-amyloidogenic status are at the highest rate while overt AD might indicate the glycoxidative cascade dwindling, ending a process possibly started two decades earlier.

Pages 97-107
Christopher Nishioka, Christina Poh, Shu-Wei Sun for the Alzheimer's Disease Neuroimaging Initiative (Handling Associate Editor: Maheen Mausoof Adamson)
Diffusion Tensor Imaging Reveals Visual Pathway Damage in Patients with Mild Cognitive Impairment and Alzheimer’s Disease
Abstract: Visual deficits are commonly seen in patients with Alzheimer's disease (AD), but postmortem histology has not found substantial damage in visual cortex regions, leading to the hypothesis that the visual pathway, from eye to the brain, may be damaged in AD. Diffusion tensor imaging (DTI) has been used to characterize white matter abnormalities. However, there is a lack of data examining the optic nerves and tracts in patients with AD. In this study, we used DTI to analyze the visual pathway in healthy controls, patients with mild cognitive impairment (MCI) and AD using scans provided by the Alzheimer's Disease Neuroimaging Initiative (ADNI). We found significant increases in the total diffusivity and radial diffusivity and reductions in fractional anisotropy in optic nerves among AD patients. Similar but less extensive changes in these metrics were seen in MCI patients as compared to controls. The differences in DTI metrics between groups mirrored changes in the splenium of the corpus callosum, which has commonly been shown to exhibit white matter damage during AD and MCI. Our findings indicate that white matter damage extends to the visual system, and may help explain the visual deficits experienced by AD patients.

Pages 109-115
Naoto Jingami, Kengo Uemura, Rio Noto, Megumi Asada, Makio Takahashi, Akihiko Ozaki, Takeshi Kihara, Takashi Kageyama, Ryosuke Takahashi, Shun Shimohama, Ayae Kinoshita
Idiopathic Normal Pressure Hydrocephalus has a Different Cerebrospinal Fluid Biomarker Profile from Alzheimer’s Disease
Abstract: The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is sometimes complicated by concomitant Alzheimer’s disease (AD) pathology. The purpose of the present study is to identify an iNPH-specific cerebrospinal fluid (CSF) biomarker dynamics and to assess its ability to differentiate iNPH from AD. Total tau (t-tau), tau phosphorylated at threonine 181 (p-tau), amyloid-β (Aβ) 42 and 40, and leucine-rich α-2-glycoprotein (LRG) were measured in 93 consecutive CSF samples consisting of 55 iNPH (46 tap test responders), 20 AD, 11 corticobasal syndrome, and 7 spinocerebeller disease. Levels of t-tau and p-tau were significantly decreased in iNPH patients especially in tap test responders compared to AD. Correlation was observed between Mini-Mental State Examination scores and Aβ42 in AD (R = 0.44) and mildly in iNPH (R = 0.28). Although Aβ42/40 ratio showed no significant difference between iNPH and AD (p = 0.08), the levels of Aβ40 and Aβ42 correlated positively with each other in iNPH (R = 0.73) but much less in AD (R = 0.26), suggesting that they have discrete amyloid clearance and pathology. LRG levels did not differ between the two. Thus, our study shows that although CSF biomarkers of iNPH patients can be affected by concomitant tau and/or amyloid pathology, CSF t-tau and p-tau are highly useful for differentiation of iNPH and AD.

Pages 117-126
Eman Khedr, Gharib Fawi, Mohammed Abd Allah Abbas, Talal A. Mohammed, Noha Abo El-Fetoh, Ghada Al Attar, Mostafa Noaman, Ahmed F. Zaki
Prevalence of Mild Cognitive Impairment and Dementia among the Elderly Population of Qena Governorate, Upper Egypt: A Community-Based Study
Abstract: Background: There are only a few reports which provide prevalence rates of mild cognitive impairment (MCI) and dementia specifically in Arabic countries. Objective: This study is aimed at estimating the prevalence of MCI and dementia among subjects aged ≥60 years using door-to-door survey in Qena Governorate/Egypt. Methods: We conducted a door-to-door survey with multistage probability random sampling. Screening of all subjects aged ≥60 years (n = 691) employed a simple questionnaire including changes in memory, behavior, and daily activity as well as the Mini-Mental State Examination. Suspected cases were referred to the hospital for full clinical examination, DSM-IV diagnostic criteria, Hachinski Ischemic Score, neuroimaging, and laboratory investigations if indicated. Results: Of the 691 participants, 12 cases had MCI, giving a crude prevalence rate (CPR) of 1.72/100 and 35 were identified as positive for dementia with a CPR of 5.07/100. The highest age-specific prevalence rates were recorded among subjects ≥ 85 years old (100/100). The CPRs were significantly higher in urban than rural areas (7.1 versus 3.27/100, respectively; p=0.03), in industrial areas than non-industrial areas (13.23 versus 1.99; p=0.00001), and in illiterate than literate participants (10.12 versus 2.25/100; p=0.00001). Conclusion: Overall, the prevalence rate of MCI and dementia were lower in Qena/Egypt than in other countries. Advanced age, illiteracy, and living in an industrial area were found to be associated with dementia.

Pages 127-138
Cristina M. Sena, Ana M. Pereira, Cristina Carvalho, Rosa Fernandes, Raquel M. Seiça, Catarina R. Oliveira, Paula I. Moreira
Type 2 Diabetes Aggravates Alzheimer’s Disease-Associated Vascular Alterations of the Aorta in Mice
Abstract: Vascular risk factors are associated with a higher incidence of dementia. In fact, diabetes mellitus is considered a main risk factor for Alzheimer’s disease (AD) and both diseases are characterized by vascular dysfunction. However, the underlying mechanisms remain largely unknown. Here, the effects of high-sucrose-induced type 2 diabetes (T2D) in the aorta of wild type (WT) and triple-transgenic AD (3xTg-AD) mice were investigated. 3xTg-AD mice showed a significant decrease in body weight and an increase in postprandial glycemia, glycated hemoglobin (HbA1c), and vascular nitrotyrosine, superoxide anion (O2•-), receptor for the advanced glycation end products (RAGE) protein, and monocyte chemoattractant protein-1 (MCP-1) levels when compared to WT mice. High-sucrose intake caused a significant increase in body weight, postprandial glycemia, HbA1c, triglycerides, plasma vascular cell adhesion molecule 1 (VCAM-1), and vascular nitrotyrosine, O2•-, RAGE, and MCP-1 levels in both WT and 3xTg-AD mice when compared to the respective control group. Also, a significant decrease in nitric oxide-dependent vasorelaxation was observed in 3xTg-AD and sucrose-treated WT mice. In conclusion, AD and T2D promote similar vascular dysfunction of the aorta, this effect being associated with elevated oxidative and nitrosative stress and inflammation. Also, AD-associated vascular alterations are potentiated by T2D. These findings support the idea that metabolic alterations predispose to the onset and progression of dementia.

Pages 139-146
Dix Meiberth*, Lukas Scheef*, Steffen Wolfsgruber, Henning Boecker, Wolfgang Block, Frank Träber, Susanne Erk, Michael T. Heneka, Heike Jacobi, Annika Spottke, Henrik Walter, Michael Wagner, Xiaochen Hu, Frank Jessen *These authors contributed equally to this work.
Cortical Thinning in Individuals with Subjective Memory Impairment
Abstract: Elderly individuals with subjective memory impairment (SMI) report memory decline, but perform within the age-, gender-, and education-adjusted normal range on neuropsychological tests. Longitudinal studies indicate SMI as a risk factor or early sign of Alzheimer’s disease (AD). There is increasing evidence from neuroimaging that at the group level, subjects with SMI display evidence of AD-related pathology. This study aimed to determine differences in cortical thickness between individuals with SMI and healthy control subjects (CO) using the FreeSurfer environment. 110 participants (41 SMI/69 CO) underwent structural 3D-T1 MR imaging. Cortical thickness values were compared between groups in predefined AD-related brain regions of the medial temporal lobe, namely the bilateral entorhinal cortex and bilateral parahippocampal cortex. Cortical thickness reduction was observed in the SMI group compared to controls in the left entorhinal cortex (p=0.012). We interpret our findings as evidence of early AD-related brain changes in persons with SMI.

Pages 147-157
Elli Kyratzi, Anastasios Liakos, Georgia Papadogiannaki, Spiros Efthimiopoulos (Handling Associate Editor: Debomoy Lahiri)
Structural and Regulatory Elements of the Interaction between Amyloid-β Protein Precursor and Homer3
Abstract: Amyloid-β protein precursor (AβPP) metabolism and the accumulation of its derivative amyloid-β (Aβ) peptide in senile plaques have been considered key players in the development of Alzheimer’s disease (AD). However, the mechanisms underlying the generation and the deposition of Aβ are not clear but emphasis has been given in the role of AβPP protein interactions that regulate its processing and offer a means to manipulate Aβ production. We have previously shown that AβPP interacts with members of the Homer protein family, which leads to inhibition of Aβ generation. Herein, we studied the structural parameters of AβPP/Homer3 interaction by analyzing the sequences and domains that play a role in the formation of the complex. We found that the cytoplasmic tail of AβPP is necessary for the interaction. Regarding Homer3, we report that both the EVH1 protein interacting domain and the polymerization coiled coil domain are essential for the complex assembly. Importantly, phosphorylation of Homers at certain serine residues seems to enhance the interaction with AβPP, possibly underlying our recent work suggesting that calcium signaling also regulates the interaction. Our results show that the regulation of AβPP/Homer3 interaction might be critical in the context of Alzheimer’s disease pathology as novel targets for regulating AβPP function and metabolism.

Pages 159-174
Martha Dlugaj, Angela Winkler, Nico Dragano, Susanne Moebus, Karl-Heinz Jöckel, Raimund Erbel, Christian Weimar on behalf of the Heinz Nixdorf Recall Study Investigative Group (Handling Associate Editor: Roberto Monastero)
Depression and Mild Cognitive Impairment in the General Population: Results of the Heinz Nixdorf Recall Study
Abstract: Background: The literature suggests an association between depression and mild cognitive impairment (MCI) and dementia, but not all studies have examined this association with regard to MCI subtypes reflecting different dementia etiologies. Objective: To examine if there is a cross-sectional relationship of depression and MCI and to examine if the relationship differs depending on the type of depression (currently elevated depressive symptoms or a positive history of lifetime depression or both) and on the MCI subtype (amnestic versus non-amnestic MCI (aMCI/naMCI)). Methods: From the second examination of the population-based Heinz Nixdorf Recall study (50% men, 50-80 years), 583 participants with MCI (aMCI n=304; naMCI n=279) and 1,446 cognitively normal participants were included in the analyses. Currently elevated depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D; score ≥18). Furthermore, participants were asked if they have ever received a previous diagnosis of depression. Log-Poisson regression models (adjusted for sociodemographic/cardiovascular risk factors) were calculated to determine the association of MCI and its subtypes with all depression variables. Results: The fully adjusted prevalence rate ratios for MCI, aMCI, and naMCI in depressed versus non-depressed participants were 2.06 (95% confidence interval, 1.60-2.64), 3.06 (2.21-4.23), and 1.93 (1.46-2.57). A positive history of lifetime depression without current depressive symptoms was solely associated with naMCI (1.31 (0.99-1.73)). Conclusion: These results suggest that the relationship of depression/depressive symptoms and MCI might differ depending on the timing of depression and on the MCI subtype. Our longitudinal follow-up will allow us to further elucidate this relationship.

Pages 175-185
Aaron M. Koenig, Isaac J. DeLozier, Michelle D. Zmuda, Megan M. Marron, Amy E. Begley, Stewart J. Anderson, Charles F. Reynolds III, Steven E. Arnold, James T. Becker, Meryl A. Butters (Guest Editor: Gwenn Smith)
Neuropsychological Functioning in the Acute and Remitted States of Late-Life Depression
Abstract: Late-life depression (LLD, major depression occurring in an adult 60 years or older) is a common condition that frequently presents with cognitive impairment. Up to half of individuals with LLD are estimated to have cognitive impairment greater than that of age- and education-matched comparators, with impairments of episodic memory, speed of information processing, executive functioning, and visuospatial ability being most common. To inform our understanding of the state- versus trait-effects of depression on neuropsychological functioning, and to overcome limitations of previous studies, we utilized baseline data from the longitudinal Pathways study to compare differences in single time point performance on a broad-based neuropsychological battery across three diagnostic groups of older adults, each comprised of unique participants (n=438): currently depressed (n=120), previously depressed but currently euthymic (n=190), and never-depressed (n=128). Consistent with our hypotheses, we found that participants with a history of depression (currently or previously depressed) performed significantly worse than never-depressed participants on most tests of global cognition, as well as on tests of episodic memory, attention and processing speed, verbal ability, and visuospatial ability; in general, differences were most pronounced within the domain of attention and processing speed. Contrary to our hypothesis, we did not observe differences in executive performance between the two depression groups, suggesting that certain aspects of executive functioning are “trait deficits” associated with LLD. These findings are in general agreement with the existing literature, and represent an enhancement in methodological rigor over previous studies given the cross-sectional approach that avoids practice effects on test performance.

Pages 187-193
Amber Watts, Robyn A. Honea, Sandra A. Billinger, Kathleen T. Rhyner, Lewis Hutfles, Eric D. Vidoni, Jeffrey M. Burns (Handling Associate Editor: Carl Eckerström)
A Combined Measure of Vascular Risk for White Matter Lesions
Abstract: Background: Though hypertension is a commonly studied risk factor for white matter lesions (WMLs), measures of blood pressure may fluctuate depending on external conditions resulting in measurement error. Indicators of arterial stiffening and reduced elasticity may be more sensitive indicators of risk for WMLs in aging; however the interdependent nature of vascular indicators creates statistical complications. Objective: The purpose of the study was to determine whether a factor score comprised of multiple vascular indicators would be a stronger predictor of WMLs than traditional measures of blood pressure. Methods: In a sample of well-characterized nondemented older adults, we used a factor analytic approach to account for variance common across multiple vascular measures while reducing measurement error. The result was a single factor score reflecting arterial stiffness and reduced elasticity. We used this factor score to predict white matter lesion volumes acquired via fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging. Results: The combined vascular factor score was a stronger predictor of deep WML (β = 0.42, p < 0.001) and periventricular WML volumes (β = 0.49, p < 0.001). After accounting for the vascular factor, systolic and diastolic blood pressure measurements were not significant predictors. Conclusions: This suggests that a combined measure of arterial elasticity and stiffening may be a stronger predictor of WMLs than systolic and diastolic blood pressure accounting for the multicollinearity associated with a variety of interrelated vascular measures.

Pages 195-204
Anthony Pinçon, Mélanie H. Thomas, Marion Huguet, Ahmad Allouche, Julie C. Colin, Alain Georges, Annabelle Derrien, Marie-Claire Lanhers, Catherine Malaplate-Armand, Thierry Oster, Catherine Corbier, Thierry Pillot, Jean Luc Olivier, Frances T. Yen (Handling Associate Editor: Monique Mulder)
Increased Susceptibility of Dyslipidemic LSR+/- Mice to Amyloid Stress is Associated with Changes in Cortical Cholesterol Levels
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease that has been linked to changes in cholesterol metabolism. Neuronal cholesterol content significantly influences the pro-apoptotic effect of amyloid-β peptide42 (Aβ42), which plays a key role in AD development. We previously reported that aged mice with reduced expression of the lipolysis stimulated lipoprotein receptor (LSR+/-), demonstrate membrane cholesterol accumulation and decreased intracellular lipid droplets in several brain regions, suggesting a potential role of LSR in brain cholesterol distribution. We questioned if these changes rendered the LSR+/- mouse more susceptible to Aβ42-induced cognitive and biochemical changes. Results revealed that intracerebroventricular injection of oligomeric Aβ42 in male 15-month old LSR+/+ and LSR+/- mice led to impairment in learning and long-term memory and decreased cortical cholesterol content of both groups; these effects were significantly amplified in the Aβ42–injected LSR+/- group. Total latency of the Morris test was significantly and negatively correlated with cortical cholesterol content of the LSR+/- mice, but not of controls. Significantly lower cortical PSD95 and SNAP-25 levels were detected in Aβ42–injected LSR+/- mice as compared to Aβ42–injected LSR+/+ mice. In addition, 24S-hydroxy cholesterol metabolite levels were significantly higher in the cortex of LSR+/- mice. Taken together, these results suggest that changes in cortex cholesterol regulation as a result of the LSR+/- genotype were linked to increased susceptibility to amyloid stress, and we would therefore propose the aged LSR+/- mouse as a new model for understanding the link between modified cholesterol regulation as risk factor for AD.

Pages 205-216
Eva Mª Arroyo-Anlló, Pierre Ingrand, Jean-Philippe Neau, Roger Gil
Procedural Learning of Semantic Categorization in Parkinson’s Disease
Abstract: This paper studies the procedural learning of semantic categorization in 29 patients with non-demented Parkinson’s disease (PD). We investigated whether the PD group was able to develop semantic skill, using a cognitive procedural task developed in our laboratory, applying a manual and serial reaction time paradigm to semantic categorization. The PD group showed similar scores to those of the control group on semantic categorization. Both groups showed reaction time reduction over the semantic procedural task, but the PD group produced longer reaction times than the control subjects. Contrary to our prediction, we observed an improvement in semantic categorization reaction times with practice, even with new verbal material for the PD patients to categorize despite their motor impairments and executive deficits. By contrast, we found a significant negative correlation between axial motor signs and the ratio of semantic procedural learning, but not for lateral motor signs. The present results support the notion that non-demented PD patients may be capable of acquiring comparable semantic skill to those of the control group.

Pages 217-233
Vasily Vorobyov, Vladimir Kaptsov, Rita Gordon, Ekaterina Makarova, Igor Podolski, Frank Sengpiel (Handling Associate Editor: Vladimir Buchman)
Neuroprotective Effects of Hydrated Fullerene C60: Cortical and Hippocampal EEG Interplay in an Amyloid-Infused Rat Model of Alzheimer’s Disease
Abstract: We studied the effects of fullerene C60 nanoparticles, namely hydrated fullerene C60 (C60HyFn), on interrelations between EEG frequency spectra from the frontal cortex and the dorsal hippocampus (CA1) on an amyloid-β (Aβ) rat model of Alzheimer’s disease (AD). Infusion of Aβ1-42 protein (1.5 µl) into the CA1 region two weeks before EEG testing diminished hippocampal theta (3.8-8.4 Hz) predominance and eliminated cortical beta (12.9-26.2 Hz) predominance observed in baseline EEG of rats infused with saline (control) or with C60HyFn alone. In contrast, these Aβ1-42 effects were abolished in rats pretreated with C60HyFn, 30 min apart. Dopaminergic mediation in AD has been shown to be involved in neuronal plasticity and Aβ transformation in different ways. To clarify its role in the cortex-hippocampus interplay in the Aβ model of AD, we used peripheral injection of a dopamine agonist, apomorphine (APO), at a low dose (0.1 mg/kg). In rats infused with C60HyFn or Aβ1-42 alone, APO attenuated the cortical beta predominance, with immediate and delayed phases evident in the Aβ1-42-rats. Pretreatment with C60HyFn diminished the APO effect in the Aβ1-42-treated rats. Thus, we show that intrahippocampal injection of Аβ1-42 dramatically disrupts cortical versus hippocampal EEG interrelations and that pretreatment with the fullerene eliminates this abnormality. We suggest that some effects of C60HyFn may be mediated through presynaptic dopamine receptors and that water-soluble C60 fullerenes have a neuroprotective potential.

Pages 235-244
Yunpeng Huang, Zhihao Wu, Bing Zhou
hSOD1 Promotes Tau Phosphorylation and Toxicity in the Drosophila Model
Abstract: Tau hyperphosphorylation has been found in several neurodegenerative diseases such as Alzheimer’s disease (AD), Down syndrome, and amyotrophic lateral sclerosis (ALS). However, factors affecting tau hyperphosphorylation are not yet clearly understood. SOD1, a Cu/Zn superoxide dismutase whose mutations can cause adult-onset ALS, is believed to be involved in the pathology of Down syndrome. In this work, the model organism Drosophila was used to study the possible link between hSOD1 and tau. Our results show that hSOD1, and to a higher degree hSOD1(A4V), can increase tau toxicity in Drosophila and exacerbate the corresponding neurodegeneration phenotype. The increased tau toxicity appears to be explainable by elevated tau phosphorylation. Tau(S2A), a tau mutant with impaired phosphorylation capabilities, does not respond to expression of hSOD1 and hSOD1(A4V). We suggest that increased SOD1 expression can lead to tau hyperphosphorylation, which might serve as an important contributing factor to the etiology of Down syndrome and SOD1-related ALS disease.

Pages 245-252
Wei Qin, Xiangfei Jia, Fen Wang, Xiumei Zuo, Liyong Wu, Aihong Zhou, Dan Li, Baoquan Min, Cuibai Wei, Yi Tang, Yi Xing, Xiumin Dong, Qi Wanga-d, Yining Gao, Ying Li, Jianping Jia (Handling Associate Editor: Hongxing Lei)
Elevated Plasma Angiogenesis Factors in Alzheimer’s Disease
Abstract: Evidence has shown that aberrant angiogenesis is an integral part of Alzheimer’s disease (AD). Angiogenesis is a complex process requiring successive activation of a rather large series of factors. The aim of this study was to determine which angiogenesis molecule(s) abnormalities were changed in plasma of AD subjects and whether plasma levels of angiogenesis factors were associated with cognitive function and risk of AD. Discovery-phase antibody arrays were used to detect plasma concentrations of 55 angiogenesis-related factors. Enzyme-linked immunosorbent assays (ELISAs) in a large cohort were further performed to identify the association of plasma angiogenesis factors with AD. We found that plasma angiogenin (ANG) and tissue inhibitor of matrix metalloproteinase-4 (TIMP-4) levels were higher in patients with AD than those in normal subjects. Significantly higher ANG and TIMP-4 were observed in the severe AD group relative to the mild AD. There were different levels of plasma ANG and TIMP-4 compared with vascular dementia and other dementias. Age or gender had no major effects on levels of these proteins. Plasma ANG and TIMP-4 levels tended to be higher in ApoE ε4 carriers compared with non-carriers, but not significantly. A multiple regression analysis after adjusting for covariates revealed correlations between plasma ANG and TIMP-4 and the MMSE and CDR. Higher plasma ANG and TIMP-4 levels were associated with significant AD risk. These results demonstrate that plasma ANG and TIMP-4 may reflect the severity of cognitive function impairment, and higher levels were associated with risk of AD.

Pages 253-268
Thomas Adi Kurnia Susanto, Emmanuel Peng Kiat Pua, Juan Zhou, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Maheen Adamson)
Cognition, Brain Atrophy, and Cerebrospinal Fluid Biomarkers Changes from Preclinical to Dementia Stage of Alzheimer’s Disease and the Influence of Apolipoprotein E
Abstract: Background: Knowledge of Alzheimer’s disease (AD) manifestation in the pre-dementia stage facilitates the selection of appropriate measures for early detection and disease progression. Objective: To examine the trajectories of cognitive performance, gray matter volume (GMV), and cerebrospinal fluid (CSF) biomarkers, together with the influence of apolipoprotein E (APOE) in subjects with amyloid-β (Aβ) deposits across the pre-clinical to dementia stages of AD. Methods: 356 subjects were dichotomized into Aβ+ and Aβ- groups based on their CSF Aβ1-42 level. We derived AD-related atrophic regions (AD-ROIs) using the voxel-based morphometry approach. We characterized the trajectories of cognitive scores, GMV at AD-ROIs, and CSF biomarkers from preclinical to disease stages in Aβ+ subjects. The effect of APOE ε4 genotype on these trajectories was examined. Results: Impairments in executive functioning/processing speed (EF/PS) and atrophy at the right supramarginal/inferior parietal gyrus were detected in cognitively normal Aβ+ subjects. Together with the APOE ε4 carrier status, these measures showed potential to identify cognitively normal elderly with abnormal CSF Aβ1-42 level in another independent cohort. Subsequently, impairment in memory, visuospatial, language, and attention as well as atrophy in the temporal lobe, thalamus, and mid-cingulate cortex were detectable in Aβ+ mild cognitive impairment (MCI) subjects. In MCI and dementia Aβ+ subjects, ε4 carriers had more severe atrophy of the medial temporal lobe and memory impairment but higher EF/PS compared to non-carriers. Conclusions: EF/PS decline and right parietal atrophy might act as non-invasive screening tests for abnormal amyloid deposition in cognitively normal elderly. APOE modulation on subsequent trajectories in cognition and atrophy should be taken into account when analyzing disease progression.

Pages 269-282
Yingni Sun, Xianfang Rong, Wenwen Lu, Ying Peng, Jiang Li, Shaofeng Xu, Ling Wang, Xiaoliang Wang
Translational Study of Alzheimer’s Disease (AD) Biomarkers from Brain Tissues in AβPP/PS1 Mice and Serum of AD Patients
Abstract: The aim of this study was to investigate potential biomarkers of Alzheimer’s disease (AD). Changes in protein expression in brain tissues from AβPP/PS1 transgenic mice were evaluated using two-dimensional gel electrophoresis combined with LC-MS/MS. A total of 23 differentially expressed proteins were successfully identified in brain tissues of which 11 were validated by western blot. Then, the levels of these differentially expressed proteins in serum from AD patients and healthy controls were examined. Of these 11 proteins, levels of 5 changed in the same direction in the serum of AD patients as they did in mouse brain: cathepsin B, VDAC1, and cofilin-2 increased, and Alix and ACAP1 decreased. Alix, cofilin-2, and ACAP1 have not been previously associated with AD. More importantly, the serum levels of Alix, cofilin-2, and ACAP1 were significantly different between AD patients and healthy controls. Furthermore, the expressions of cathepsin B, cofilin-2, VDAC1, and ACAP1 strongly correlated with the Mini-Mental State Examination scores of the AD patients. The results indicate that these proteins are putative biomarkers of AD which may be useful in its diagnosis and in the evaluation of new anti-AD drugs both in pre-clinical and clinical studies.

Pages 283-293
Shunichiro Shinagawa, Shinichiro Nakajima, Eric Plitman, Ariel Graff-Guerrero, Masaru Mimura, Kazuhiko Nakayama, Bruce L Miller
Non-Pharmacological Management for Patients with Frontotemporal Dementia: A Systematic Review
Abstract: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by changes in behavior and language caused by focal degeneration of the frontal and anterior temporal lobes. The behavioral symptoms are distressing to patients and their caregivers. Non-pharmacological management is important as no disease-specific pharmacological treatment for FTD is currently available. The primary objective is to review the literature on non-pharmacological management for FTD and to propose directions for future research, with reference to findings. A search was performed using PubMed, MEDLINE, and EMBASE. Search terms included “frontotemporal dementia”, and words related to non-pharmacological management, and it identified a total of 858 articles. Results revealed that very few randomized controlled trials exist on non-pharmacological management interventions for FTD. These interventions have been proposed by literature based on clinical experience. A small number of studies have supported behavioral management techniques that exploit disease-specific behaviors and preserved functions in patients with FTD, along with the management of caregivers’ distress. These limitations warrant well-designed large-scale research to examine effects of non-pharmacological interventions on behavioral symptoms of FTD.

Pages 295-304
Ruben Muñiz, Cristina Massegú Serra, Barry Reisberg, José Manuel Rojo, Teodoro del Ser, Jordi Peña Casanova, Javier Olazarán
Cognitive-Motor Intervention in Alzheimer’s Disease: Long-Term Results from the Maria Wolff Trial
Abstract: Background. Little is known about the long-term acceptance and effects of cognitive and motor stimulation interventions (CMSI) in Alzheimer’s disease (AD). Objective. To evaluate a replicable CMSI program for mild cognitive impairment (MCI) and mild-to-moderate AD persons. Methods. Eighty-four non-institutionalized subjects with AD were randomized to receive either CMSI, administered by a single care provider, or standard support. Cognition, activities of daily living (ADL), mood, and study partner’s subjective burden were assessed by blinded raters. Data on institutionalization, psychiatric medications, and demise were collected by the study physicians. Random effects model and survival analyses were conducted, after 2 and 3 years of study. Results. Three-year assessments could be performed by the physician in 85% and by the blinded rater in 66% of subjects. Significant benefits were observed in basic ADL at the 2- and 3-year assessments, whereas instrumental ADL showed benefits only up to the second year of intervention (p<0.05). Conclusion. Long-term cognitive-motor stimulation is well accepted and produces functional benefits in subjects with AD, with no extra subjective burden in the partner.

Pages 305-318
Heather M. Wilkins, Steven M. Carl, Sam G. Weber, Suruchi A. Ramanujan, Barry W. Festoff, Daniel A. Linseman, Russell H. Swerdlow
Mitochondrial Lysates Induce Inflammation and Alzheimer’s Disease-Relevant Changes in Microglial and Neuronal Cells
Abstract: Neuroinflammation occurs in Alzheimer’s disease (AD). While AD genetic studies implicate inflammation-relevant genes and fibrillar amyloid-β protein promotes inflammation, our understanding of AD neuroinflammation nevertheless remains incomplete. In this study we hypothesized damage-associated molecular pattern (DAMP) molecules arising from mitochondria, intracellular organelles that resemble bacteria, could contribute to AD neuroinflammation. To preliminarily test this possibility, we exposed neuronal and microglial cell lines to enriched mitochondrial lysates. BV2 microglial cells treated with mitochondrial lysates showed decreased TREM2 mRNA, increased TNFα mRNA, increased MMP-8 mRNA, increased IL-8 mRNA, redistribution of NFκB to the nucleus, and increased p38 MAPK phosphorylation. SH-SY5Y neuronal cells treated with mitochondrial lysates showed increased TNFα mRNA, increased NFκB protein, decreased IκBα protein, increased AβPP mRNA, and increased AβPP protein. Enriched mitochondrial lysates from SH-SY5Y cells lacking detectable mitochondrial DNA (ρ0 cells) failed to induce any of these changes, while mtDNA obtained directly from mitochondria (but not PCR-amplified mtDNA) increased BV2 cell TNFα mRNA. These results indicate at least one mitochondrial-derived DAMP molecule, mtDNA, can induce inflammatory changes in microglial and neuronal cell lines. Our data are consistent with the hypothesis that a mitochondrial-derived DAMP molecule or molecules could contribute to AD neuroinflammation.