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Volume 57, Number 2, 2017

Pages 317-330
Review

Morgan Robinson, Brenda Y. Lee, Francis T. Hane
Recent Progress in Alzheimer’s Disease Research, Part 2: Genetics and Epidemiology
Abstract: This is the second part of a three-part review series reviewing the most important advances in Alzheimer’s disease (AD) research since 2010. This review covers the latest research on genetics and epidemiology. Epidemiological and genetic studies are revealing important insights into the etiology of, and factors that contribute to AD, as well as areas of priority for research into mechanisms and interventions. The widespread adoption of genome wide association studies has provided compelling evidence of the genetic complexity of AD with genes associated with such diverse physiological function as immunity and lipid metabolism being implicated in AD pathogenesis.

Pages 331-352
Review

Max Toepper
Dissociating Normal Aging from Alzheimer’s Disease: A View from Cognitive Neuroscience
Abstract: Both normal aging and Alzheimer’s disease (AD) are associated with changes in cognition, grey and white matter volume, white matter integrity, neural activation, functional connectivity, and neurotransmission. Obviously, all of these changes are more pronounced in AD and proceed faster providing the basis for an AD diagnosis. Since these differences are quantitative, however, it was hypothesized that AD might simply reflect an accelerated aging process. The present article highlights the different neurocognitive changes associated with normal aging and AD and shows that, next to quantitative differences, there are multiple qualitative differences as well. These differences comprise different neurocognitive dissociations as different cognitive deficit profiles, different weights of grey and white matter atrophy, and different gradients of structural decline. These qualitative differences clearly indicate that AD cannot be simply described as accelerated aging process but on the contrary represents a solid entity.

Pages 353-371
Hypothesis
Jack C. de la Torre (Handling Associate Editor: Patrizia Mecocci)
Are Major Dementias Triggered by Poor Blood Flow to the Brain? Theoretical Considerations
Abstract: There is growing evidence that chronic brain hypoperfusion plays a central role in the development of Alzheimer’s disease (AD) long before dyscognitive symptoms or amyloid-β accumulation in the brain appear. This commentary proposes that dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD) may also develop from chronic brain hypoperfusion following a similar but not identical neurometabolic breakdown as AD. The argument to support this conclusion is that chronic brain hypoperfusion, which is found at the early stages of the three dementias reviewed here, will reduce oxygen delivery and lower oxidative phosphorylation promoting a steady decline in the synthesis of the cell energy fuel adenosine triphosphate (ATP). This process is known to lead to oxidative stress. Virtually all neurodegenerative diseases, including FTD, DLB, and CJD, are characterized by oxidative stress that promotes inclusion bodies which differ in structure, location, and origin, as well as which neurological disorder they typify. Inclusion bodies have one thing in common; they are known to diminish autophagic activity, the protective intracellular degradative process that removes malformed proteins, protein aggregates, and damaged subcellular organelles that can disrupt neuronal homeostasis. Neurons are dependent on autophagy for their normal function and survival. When autophagic activity is diminished or impaired in neurons, high levels of unfolded or misfolded proteins overwhelm and downregulate the neuroprotective activity of unfolded protein response which is unable to get rid of dysfunctional organelles such as damaged mitochondria and malformed proteins at the synapse. The endpoint of this neuropathologic process results in damaged synapses, impaired neurotransmission, cognitive decline, and dementia.

Pages 373-386
Amani Alghamdi, Julie Vallortigara, David R. Howlett, Martin Broadstock, Tibor Hortobágyi, Clive Ballard, Alan J. Thomas, John T. O’Brien, Dag Aarsland, Johannes Attems, Paul T. Francis, David R. Whitfield (Handling Associate Editor: Steffany Bennett)
Reduction of RPT6/S8 (a Proteasome Component) and Proteasome Activity in the Cortex is associated with Cognitive Impairment in Lewy Body Dementia
Abstract: Lewy body dementia is the second most common neurodegenerative dementia and is pathologically characterized by α-synuclein positive cytoplasmic inclusions, with varying amounts of amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived proteins, may be a mediating factor of disease progression and of the development of α-synuclein aggregates. In the present study, protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined. Furthermore, the main proteolytic-like (chymotrypsin- and PGPH-) activities have also been analyzed. The middle frontal (Brodmann, BA9), inferior parietal (BA40), and anterior cingulate (BA24) gyrus’ cortex were selected as regions of interest from Parkinson’s disease dementia (PDD, n=31), dementia with Lewy bodies (DLB, n=44), Alzheimer’s disease (AD, n=16), and control (n=24) brains. Clinical and pathological data available included the MMSE score. DLB, PDD, and AD were characterized by significant reductions of RPT6 (one-way ANOVA, p < 0.001; Bonferroni post hoc test) in prefrontal cortex and parietal cortex compared with controls. Strong associations were observed between RPT6 levels in prefrontal, parietal cortex, and anterior cingulate gyrus and cognitive impairment (p = 0.001, p = 0.001, and p = 0.008, respectively). These findings highlight the involvement of the UPS in Lewy body dementia and indicate that targeting the UPS may have the potential to slow down or reduce the progression of cognitive impairment in DLB and PDD.

Pages 387-393
Victor Bloniecki Dag Aarsland, Kaj Blennow, Jeffrey Cummings, Farshad Falahati, Bengt Winblad, Yvonne Freund-Levi
Effects of Risperidone and Galantamine Treatment on Alzheimer’s Disease Biomarker Levels in Cerebrospinal Fluid
Abstract: Background: Treatment for neuropsychiatric symptoms (NPS) in dementia is insufficient. Antipsychotics and acetylcholinesterase inhibitors are used generating symptomatic improvements in behavior and cognition, but few studies have investigated their effect on Alzheimer’s disease (AD) biomarkers in cerebrospinal fluid (CSF). Objective: This is a secondary analysis based on an earlier clinical trial comparing the treatment effects on NPS. The aim of this study was to examine whether treatment with risperidone and galantamine affect levels of the biomarkers T-Tau, P-Tau, Aβ1-42, and Aβ42/40-ratio in CSF. The secondary aim was to test if baseline levels of these biomarkers are associated with the clinical course of NPS. Methods: 83 patients (mean + SD 77.9.6±7.7 years) with dementia and NPS were randomized to galantamine (n=44) or risperidone (n=39) treatment. CSF samples were collected at baseline and after 12 weeks. Results: Changes in levels of biomarkers between the two treatment groups did not differ significantly. Low baseline levels of Aβ1-42 was significantly associated with reduction of irritability at follow up. Low baseline levels of Aβ1-42, Aβ42/40, and P-Tau were significant correlates of reduction in appetite and eating disorders. CSF Aβ1-42 levels in patients treated with risperidone were significantly decreased at follow up, showing an 8% (40 pg/mL) reduction as compared with baseline (p=0.03). Conclusions: Our results suggest that risperidone may affect the CSF profile of AD biomarkers indicating more amyloid pathology. Treatment with galantamine did not affect the CSF biomarkers in any direction. The AD CSF biomarkers displayed correlations with specific NPS suggesting potential research questions to be pursued.

Pages 395-409
Yin Li, Ze-Xu Li, Tan Jin, Zhan-You Wang, Pu Zhao
Tau Pathology Promotes the Reorganization of the Extracellular Matrix and Inhibits the Formation of Perineuronal Nets by Regulating the Expression and the Distribution of Hyaluronic Acid Synthases
Abstract: Hyaluronic acid (HA) is the backbone of the extracellular matrix (ECM) and provides biochemical and physical support to aggrecan-based perineuronal nets (PNNs), which are associated with the selective vulnerability of neurons in Alzheimer’s disease (AD). Here, we showed that HA synthases (HASs), including Has1, Has2, and Has3, were widely expressed in murine central nervous system. All types of HASs were localized to cell bodies of neurons; only Has1 existed in the membranes of neural axons. By using TauP301S transgenic (Tg) mouse model, we found that the axonal-localization of Has1 was abolished in TauP301S overexpressed mouse brain, and the redistribution of Has1 was also observed in human AD brains, suggesting that the localization of Has1 is dependent on intact microtubules which are regulated partially by the phosphorylation and dephosphorylation cycles of tau proteins. Furthermore, Has1 was reduced and Has3 was increased in TauP301S Tg mouse brain, resulting in the upregulation of shorter-chain HA in the ECM. These findings suggest that by abolishing the axonal-localization of Has1 and promoting the expression of Has3 and the synthesis of shorter-chain HA, the tau pathology breaks the balance of ECM components, promotes the reorganization of the ECM, and inhibits the formation of PNNs in the hippocampus, and then regulates neuronal plasticity during the progression of AD.

Pages 411-422
Simone Hollands, Yen Ying Lim, Simon M. Laws, Victor L. Villemagne, Robert H. Pietrzak, Karra Harrington, Tenielle Porter, Peter Snyder, David Ames, Christopher Fowler, Stephanie R. Rainey-Smith, Ralph N. Martins, Olivier Salvado, Joanne Robertson, Christopher C. Rowe, Colin L. Masters, Paul Maruff, for the AIBL Research Group
APOE ε4 Genotype, Amyloid, and Clinical Disease Progression in Cognitively Normal Older Adults
Abstract: Background: In cognitively normal (CN) older adults, carriage of the apolipoprotein E (APOE) ε4 allele is associated with increased risk for dementia of the Alzheimer type (AD-dementia). It is unclear whether this occurs solely through APOE ε4 increasing amyloid-β (Aβ) accumulation or through processes independent of Aβ. Objective: To determine the extent and nature to which APOE 4 increases risk for clinical disease progression in CN older adults. Methods: Data from the total (n=765) and Aβ-imaged (n=423) CN cohort in the Australian Imaging, Biomarker and Lifestyle (AIBL) Study of Ageing was analyzed using Cox proportional hazard models to estimate ε4 risk for clinical disease progression over a 72-month follow-up. Results: With Aβ status unknown and risk from demographic characteristics controlled, 4 carriage increased risk for clinical disease progression over 72 months by 2.66 times compared to risk of non-4 carriage. Re-analysis with Aβ status included showed that abnormally high Aβ increased risk for clinical disease progression over 72 months by 2.11 times compared to risk of low Aβ. However, with Aβ level known, 4 carriage was no longer predictive of clinical disease progression. Conclusion: In CN older adults, the risk of 4 for clinical disease progression occurs through the effect of 4 increasing Aβ levels.

Pages 423-436
Shea J. Andrews, Debjani Das, Kaarin J. Anstey, Simon Easteal (Handling Associate Editor: Corinne Engelman)
Late Onset Alzheimer’s Disease Risk Variants in Cognitive Decline: The PATH Through Life Study
Abstract: Recent genome wide association studies have identified a number of single nucleotide polymorphisms associated with late onset Alzheimer’s disease (LOAD). We examined the associations of 24 LOAD risk loci, individually and collectively as a genetic risk score, with cognitive function. We used data from 1,626 non-demented older Australians of European ancestry who were examined up to four times over 12 years on tests assessing episodic memory, working memory, vocabulary, and information processing speed. Linear mixed models were generated to examine associations between genetic factors and cognitive performance. Twelve SNPs were significantly associated with baseline cognitive performance (ABCA7, MS4A4E, SORL1), linear rate of change (APOE, ABCA7, INPP5D, ZCWPW1, CELF1), or quadratic rate of change (APOE, CLU, EPHA1, HLA-DRB5, INPP5D, FERMT2). In addition, a weighted genetic risk score was associated with linear rate of change in episodic memory and information processing speed. Our results suggest that a minority of AD related SNPs may be associated with non-clinical cognitive decline. Further research is required to verify these results and to examine the effect of preclinical AD in genetic association studies of cognitive decline. The identification of LOAD risk loci associated with non-clinical cognitive performance may help in screening for individuals at greater risk of cognitive decline.

Pages 437-445
Christelle Gervaise-Henry, Gasshan Watfa, Eliane Albuisson, Allan Kolodziej, Brigitte Dousset, Jean-Luc Olivier, Thérèse Rivasseau Jonveaux, Catherine Malaplate-Armand
Cerebrospinal Fluid Aβ42/Aβ40 as a Means to Limiting Tube- and Storage-Dependent Pre-Analytical Variability in Clinical Setting
Abstract: Background: Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers have recently been included in the criteria for AD diagnosis. Unfortunately, their wider use in routine and interpretation require more standardization, particularly for the pre-analytical steps. In particular, amyloid-β (Aβ)42 peptide measurement is strongly influenced by the type of collection tube and by repeated freeze/thaw cycles. Objective. The objectives of this study were to compare, the in clinical setting, the impact of collection tubes and the repetition of freeze/thaw cycles on Aβ42 and Aβ40 concentrations and consequently determine if the Aβ42/Aβ40 ratio could resolve the diagnosis difficulties related to these pre-analytical parameters. Methods. CSF from 35 patients was collected in different polypropylene (PP) tubes and stored at -80°C after sampling. For CSF collected in the reference tube, three successive freeze-thaw cycles were done. Aβ42 and Aβ40 concentrations were determined in each condition in order to calculate the Aβ42/Aβ40 ratio. Results. Our results showed that CSF Aβ42 and Aβ40 values were significantly different according to the type of collection tube and the number of freeze/thaw cycles. Although the calculation of the Aβ42/Aβ40 ratio eliminated the effect of PP tube-dependent variation, this was not the case for freeze-thaw cycle-associated variation. Conclusion. The use of Aβ42/Aβ40 ratio rather than Aβ42 alone could contribute toward pre-analytical standardization, thus allowing the general use of CSF AD biomarkers in routine practice.

Pages 447-459
Ana Espinosa, Montserrat Alegreta, Pedro Pesini, Sergi Valero, Asunción Lafuente, Mar Buendía, Itziar San José, Marta Ibarria, Miguel A. Tejero, Joan Giménez, Susana Ruiz, Isabel Hernández, Francesc Pujadas, Pablo Martínez-Lage, Josep Munuera, Javier Arbizu, Lluis Tárraga, Suzanne B. Hendrix, Agustín Ruiz, James T. Becker, Susan M. Landau, Oscar Sotolongo-Grau, Manuel Sarasa, Mercè Boada, for the AB255 Study Group, for the Alzheimer’s Disease Neuroimaging Initiative
Cognitive Composites Domain Scores Related to Neuroimaging Biomarkers within Probable-Amnestic Mild Cognitive Impairment-Storage Subtype
Abstract: The probable-amnestic (Pr-a) mild cognitive impairment (MCI)-storage subtype is a phenotype with 8.5 times more risk of conversion to dementia, mainly Alzheimer’s disease (AD), than the possible non-amnestic (Pss-na) MCI. The aim of this study was to find the optimized cognitive composites (CCs) domain scores most related to neuroimaging biomarkers within Pr-aMCI-storage subtype patients. The Fundació ACE (ACE) study with 20 Pr-aMCI-storage subtype subjects (MCI) were analyzed. All subjects underwent a neuropsychological assessment, a structural MRI, FDG-PET, and PIB-PET. The adjusted hippocampal volume (aHV) on MRI, the standard uptake value ratio (SUVR) on FDG-PET and PIB-PET SUVR measures were analyzed. The construction of the CCs domain scores, and the aHV on MRI and FDG-PET SUVR measures, were replicated in the parental AB255 study database (n=133 MCI). Partial correlations adjusted by age, gender, and education were calculated with the associated p-value among every CC domain score and the neuroimaging biomarkers. The results were replicated in the “MCI due to AD” with memory storage impairments from ADNI. Delayed Recall CC domain score was significantly correlated with PIB-PET SUVR (β= -0.61, p=0.003) in the ACE study and also with aHV on MRI (β= 0.27, p=0.01) and FDG-PET SUVR (β= 0.27, p=0.01) in the AB255 study. After a median survival time of 20.6 months, 85% from the ACE MCI converted to AD. The replication of our results in the ADNI dataset also confirmed our findings. Delayed Recall is the CC domain score best correlated with neuroimaging biomarkers associated with prodromal AD diagnosis.

Pages 461-473
José-Carlos Delgado-González, José Florensa-Vila, Francisco Mansilla-Legorburo, Ricardo Insausti Emilio Artacho-Pérula
Magnetic Resonance Imaging and Anatomical Correlation of Human Temporal Lobe Landmarks, in 3D Euclidean Space: A Study of Control and Alzheimer’s Disease Subjects
Abstract: Background: The medial temporal lobe (MTL), and in particular the hippocampal formation, is essential in the processing and consolidation of declarative memory. The 3D environment of the anatomical structures contained in the MTL is an important issue. Objective: Our aim was to explore the spatial relationship of the anatomical structures of the MTL and changes in aging and/or Alzheimer’s disease (AD). Methods: MTL anatomical landmarks are identified and registered to create a 3D network. The brain network is quantitatively described as a plane, rostrocaudally-oriented, and presenting Euclidean/real distances. Correspondence between 1.5T RM, 3T RM, and histological sections were assessed to determine the most important recognizable changes in AD, based on statistical significance. Results: In both 1.5T and 3T RM images and histology, inter-rater reliability was high. Sex and hemisphere had no influence on network pattern. Minor changes were found in relation to aging. Distances from the temporal pole to the dentate gyrus showed the most significant differences when comparing control and AD groups. The best discriminative distance between control and AD cases was found in the temporal pole/dentate gyrus rostrocaudal length in histological sections. Moreover, more distances between landmarks were required to obtain 100% discrimination between control (divided into 65 years) and AD cases. Discussion: Changes in the distance between MTL anatomical landmarks can successfully be detected by using measurements of 3D network patterns in control and AD cases.

Pages 475-482
Lixia Yu, Weiguang Wang, Wei Pang, Zhonghai Xiao, Yugang Jiang, Yan Hong
Dietary Lycopene Supplementation Improves Cognitive Performances in Tau Transgenic Mice Expressing P301L Mutation via Inhibiting Oxidative Stress and Tau Hyperphosphorylation
Abstract: Background: Oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD) and other tauopathies and participates in their development by promoting hyperphosphorylation of microtubule-associated protein tau. Lycopene, as an effective antioxidant, combined with vitamin E seemed to be additive against oxidative stress. Objective: The present study was undertaken to examine whether lycopene or lycopene/vitamin E could exert protective effects on memory deficit and oxidative stress in tau transgenic mice expressing P301L mutation. Materials and methods: P301L transgenic mice were assigned to three groups: P301L group (P301L), P301L+lycopene (Lyc), and P301L+lycopene/vitamin E (Lyc+VE). Age-matched C57BL/6J mice as wild type controls (Con) were used in the present study. Spatial memory was assessed by radial arm while passive memories were evaluated by step-down and step-through tests. Levels of tau phosphorylation were detected by western blot. Oxidative stress biomarkers were measured in the serum using biochemical assay kits. Results: Compared with the control group, P301L mice displayed significant spatial and passive memory impairments, elevated malondialdehyde (MDA) levels and decreased glutathione peroxidase (GSH-Px) activities in serum, and increased tau phosphorylation at Thr231/Ser235, Ser262, and Ser396 in brain. Supplementations of lycopene or lycopene/vitamin E could significantly ameliorate the memory deficits, observably decreased MDA concentrations and increased GSH-Px activities, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites. Conclusions: Our findings indicated that the combination of lycopene and vitamin E antioxidants acted in a synergistic fashion to bring significant effects against oxidative stress in tauopathies.

Pages 483-491
Javier Riancho, José Luis Vázquez-Higuera, Ana Pozueta, Carmen Lage, Martha Kazimierczak, María Bravo, Miguel Calero, Andrea González, Eloy Rodríguez, Alberto Lleó, Pascual Sánchez-Juan
MicroRNA Profile in Patients with Alzheimer’s Disease: Analysis of miR-9-5p and miR-598 in Raw and Exosome Enriched Cerebrospinal Fluid Samples
Abstract: Background: MicroRNAs have been postulated as potential biomarkers for Alzheimer’s disease (AD). Exosomes are nanovesicles which transport microRNAs, proteins, and other cargos. It has been hypothesized that the exosome traffic might be increased in neurodegenerative disorders. Objective: i) To assess the cerebrospinal fluid (CSF) microRNA profile in a group of AD patients and control subjects and to validate a group of microRNAs previously reported by other authors. ii) To compare microRNA levels in whole CSF and in the exosome-enriched fraction in AD patients. Methods: A panel of 760 microRNAs was analyzed in the CSF of 10 AD patients and 10 healthy subjects. Among microRNAs differently expressed, we selected those that had been previously reported by other authors. Candidates were validated in a larger group by individual qPCR assays. MicroRNA expression was also evaluated in exosome-enriched CSF samples of patients with AD and controls. Results: Fifteen microRNAs were differently expressed in AD. MiR-9-5p, miR-134, and miR-598 were selected as candidates for further analysis. MiR-9-5p and miR-598 were detected in 50 and 75% of control CSF samples, respectively, while they were not detected in any AD CSF samples. We observed an opposite pattern when we evaluated the microRNA expression in the exosome-enriched CSF AD samples. No pattern variations were noted among healthy subjects. Conclusion: These data propose miR-9-5p and miR-598 as potential biomarkers for AD. Further studies in plasma and other body fluids will confirm their potential role as easily accessible biomarkers. In addition, our data suggest that exosome trafficking is different between AD and control subjects raising the need to take this phenomenon into consideration in future studies of AD biomarkers.

Pages 493-504
Herbert Oberacher, Kathrin Arnhard, Caroline Linhart, Angela Diwo, Josef Marksteiner, Christian Humpel
Targeted Metabolomic Analysis of Soluble Lysates from Platelets of Patients with Mild Cognitive Impairment and Alzheimer’s Disease Compared to Healthy Controls: Is PC aeC40:4 a Promising Diagnostic Tool?
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system. The use of biological fluids in AD diagnosis remains limited to the analysis of specific protein biomarkers in cerebrospinal fluid. However, metabolomic analysis has recently revealed several metabolites in plasma, especially phosphatidylcholines (PC), as putative biomarkers specific for AD. Following on previous reports of platelet abnormalities in AD, we hypothesized that platelets metabolites released in plasma may offer new biomarkers in AD. The aim of the present study was to apply targeted metabolomics to compare metabolites in soluble lysates of platelets from healthy controls (CO), patients with mild cognitive impairment (MCI), and patients with AD in a cohort of 90 subjects. We could target 163 metabolites and quantitative data were obtained for 91 metabolites. Among these, the lipid PC aeC40:4 significantly differentiated AD from CO (p=0.0009), while four other lipids (PC aaC32:0, PC ae C32:2, PC aeC34:1, and SM(OH)C14:1) differentiated patients with MCI from CO. The combination of three phosphatidylcholines (PC aeC32:2, PC aeC34:1, PCaaC36:5), two lyso-phosphatidylcholines (lysoPC aC18:1, lysoPC aC16:0), and one sphingomyelin (SM(OH) C14:1) constructed a valuable prediction model using the C4.5 decision tree. The diagnosis accuracy for AD versus CO and MCI was 85%. In a blinded follow up conversion study (10 patients with a second blood collection after 9 months), we could verify the clinical diagnosis in 19 out of 20 cases. We propose that soluble platelet PCaeC40:4 is a promising marker to diagnose AD with a cut-off of

Pages 505-518
Ce Zhang, Yiying Zhang, Yuan Shen, Guoqing Zhao, Zhongcong Xie, Yuanlin Dong (Handling Associate Editor: Xuemin Xu)
Anesthesia/Surgery Induces Cognitive Impairment Only in Female Alzheimer’s Disease Transgenic Mice
Abstract: Anesthesia and/or surgery may promote Alzheimer’s disease (AD) by accelerating its neuropathogenesis. Other studies showed different findings. However, the potential sex difference among these studies has not been well considered, and it is unknown whether male or female AD patients are more vulnerable to develop postoperative cognitive dysfunction. We therefore set out to perform a proof of concept study to determine whether anesthesia and surgery can have different effects in male and female AD transgenic (Tg) mice, and in female AD Tg plus Cyclophilin D knockout (CypD KO) mice. The mice received an abdominal surgery under sevoflurane anesthesia (anesthesia/surgery). Fear Conditioning System (FCS) was used to assess the cognitive function. Hippocampal levels of synaptic marker postsynaptic density 95 (PSD-95) and synaptophysin (SVP) were measured using western blot analysis. Here we showed that the anesthesia/surgery decreased the freezing time in context test of FCS at 7 days after the anesthesia/surgery in female, but not male, mice. The anesthesia/surgery reduced hippocampus levels of synaptic marker PSD-95 and SVP in female, but not male, mice. The anesthesia/surgery induced neither reduction in freezing time in FCS nor decreased hippocampus levels of PSD-95 and SVP in the AD Tg plus CypD KO mice. These data suggest that the anesthesia/surgery induced a sex-dependent cognitive impairment and reduction in hippocampus levels of synaptic markers in AD Tg mice, potentially via a mitochondria-associated mechanism. These findings could promote clinical investigations to determine whether female AD patients are more vulnerable to the development of postoperative cognitive dysfunction.

Pages 519-530
Eric Heuer, Jessica Jacobs, Rebecca Du, Silun Wang, Orion P. Keifer Jr., Amarallys F. Cintron, Jeromy Dooyema, Yuguang Meng, Xiaodong Zhang, Lary C. Walker
Amyloid-Related Imaging Abnormalities in an Aged Squirrel Monkey with Cerebral Amyloid Angiopathy
Abstract: Amyloid-related imaging abnormalities (ARIA) in magnetic resonance imaging scans have emerged as indicators of potentially serious side effects in clinical trials of therapeutics for Alzheimer’s disease. These anomalies include an edematous type (ARIA-E) that appears as hyperintense (bright) regions by T2-weighted MRI, and a type characterized by the deposition of hemosiderin (ARIA-H) that elicits a hypointense signal, especially in T2* susceptibility-weighted imaging. ARIA in general has been linked to the presence of amyloid-β (Aβ)-type cerebral amyloid angiopathy, an accumulation of misfolded Aβ protein in the vascular wall that impairs the integrity of brain blood vessels. However, the pathobiology of ARIA remains poorly understood, in part due to the absence of an animal model of the disorder that would enable a contemporaneous analysis of tissue integrity in the affected region. Here we describe both ARIA-E and ARIA-H in an aged squirrel monkey (Saimiri sciureus), a nonhuman primate model of naturally occurring cerebral amyloid angiopathy. Histopathologic examination of the anomalous region revealed reactive astrocytosis and microgliosis, infiltration of systemic inflammatory/immune cells, damage to axons and myelin, and hemosiderin deposition. The disruption of axons in particular suggests that ARIA-E could have functional consequences for affected regions. The squirrel monkey model can be useful for studying the pathogenesis and long-term effects of ARIA, and for testing the safety and efficacy of emerging therapies for Alzheimer’s disease.

Pages 531-540
Amelie T. van der Ven, Julius C. Pape, Dirk Hermann, Robert Schloesser, Just Genius, Nadine Fischer, Rainald Mößner, Norbert Scherbaum, Jens Wiltfang, Dan Rujescu, Jens Benninghoff (Handling Associate Editor: Piotr Lewczuk)
Methylene Blue (Tetramethylthionine Chloride) Influences the Mobility of Adult Neural Stem Cells: A Potentially Novel Therapeutic Mechanism of a Therapeutic Approach in the Treatment of Alzheimer’s Disease
Abstract: An interest in neurogenesis in the adult human brain as a relevant and targetable process has emerged as a potential treatment option for Alzheimer’s disease and other neurodegenerative conditions. The aim of this study was to investigate the effects of tetramethylthionine chloride (methylene blue, MB) on properties of adult murine neural stem cells. Based on recent clinical studies, MB has increasingly been discussed as a potential treatment for Alzheimer’s disease. While no differences in the proliferative capacity were identified, a general potential of MB in modulating the migratory capacity of adult neural stem cells was indicated in a cell mobility assay. To our knowledge, this is the first time that MB could be associated with neural mobility. The results of this study add insight to the spectrum of features of MB within the central nervous system and may be helpful for understanding the molecular mechanisms underlying a potential therapeutic effect of MB.

Pages 541-556
Matteo De Marco, Davide Duzzi, Francesca Meneghello, Annalena Venneri
Cognitive Efficiency in Alzheimer’s Disease is Associated with Increased Occipital Connectivity
Abstract: There are cognitive domains which remain fully functional in a proportion of Alzheimer’s disease (AD) patients. It is unknown, however, what distinctive mechanisms sustain such efficient processing. The concept of “cognitive efficiency” was investigated in these patients by operationalizing it as a function of the level of performance shown on the Letter Fluency test, on which, very often, patients in the early stages of AD show unimpaired performance. Forty-five individuals at the prodromal/early stage of AD (diagnosis supported by subsequent clinical follow-ups) and 45 healthy controls completed a battery of neuropsychological tests and an MRI protocol which included resting state acquisitions. The Letter Fluency test was the only task on which no between-group difference in performance was found. Participants were divided into “low-performing” and “high-performing” according to the global median. Dual-regression methods were implemented to compute six patterns of network connectivity. The diagnosis-by-level of performance interaction was inferred on each pattern to determine the network distinctiveness of efficient performance in AD. Significant interactions were found in the anterior default mode network, and in both left and right executive control networks. For all three circuits, high-performing patients showed increased connectivity within the ventral and dorsal part of BA19, as confirmed by post-hoc t tests. Peristriate remapping is suggested to play a compensatory role. Since the occipital lobe is the neurophysiological source of long-range cortical connectivity, it is speculated that the physiological mechanisms of functional connectivity might sustain occipital functional remapping in early AD, particularly for those functions which are sustained by areas not excessively affected by the prodromal disease.

Pages 557-573
Nzeera Ketter, H. Robert Brashear, Jennifer Bogert, Jianing Di, Yves Miaux, Achim Gass, Derk D. Purcell, Frederik Barkhof, H. Michael Arrighi
Central Review of Amyloid-Related Imaging Abnormalities in Two Phase III Clinical Trials of Bapineuzumab in Mild-To-Moderate Alzheimer’s Disease Patients
Abstract: Background: Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]). Objectives: To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer’s disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE 4 allele carriers or noncarriers). Methods: Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE 4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is described. Results: In the Final Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE 4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs

Pages 575-601
Caroline Dallaire-Théroux, Brandy L. Callahan, Olivier Potvin, Stephan Saikali, Simon Duchesne
Radiological-Pathological Correlation in Alzheimer’s Disease: Systematic Review of Antemortem Magnetic Resonance Imaging Findings
Abstract: Background: The standard method of ascertaining Alzheimer’s disease (AD) remains postmortem assessment of amyloid plaques and neurofibrillary degeneration. Vascular pathology, Lewy bodies, TDP-43, and hippocampal sclerosis are frequent comorbidities. There is therefore a need for biomarkers that can assess these etiologies and provide a diagnosis in vivo. Objective: We conducted a systematic review of published radiological-pathological correlation studies to determine the relationship between antemortem magnetic resonance imaging (MRI) and neuropathological findings in AD. Methods: We explored PubMed in June-July 2015 using “Alzheimer’s disease” and combinations of radiological and pathological terms. After exclusion following screening and full-text assessment of the 552 extracted manuscripts, three others were added from their reference list. In the end, we report results based on 27 articles. Results: Independently of normal age-related brain atrophy, AD pathology is associated with whole-brain and hippocampal atrophy and ventricular expansion as observed on T1-weighted images. Moreover, cerebral amyloid angiopathy and cortical microinfarcts are also related to brain volume loss in AD. Hippocampal sclerosis and TDP-43 are associated with hippocampal and medial temporal lobe atrophy, respectively. Brain volume loss correlates more strongly with tangles than with any other pathological finding. White matter hyperintensities observed on proton density, T2-weighted and FLAIR images are strongly related to vascular pathologies, but are also associated with other histological changes such as gliosis or demyelination. Conclusion: Cerebral atrophy and white matter changes in the living brain reflect underlying neuropathology and may be detectable using antemortem MRI. In vivo MRI may therefore be an avenue for AD pathological staging.

Pages 603-611
Iris Rawtaer, Qi Gao, Ma Shwe Zin Nyunt, Lei Feng, Mei Sian Chong, Wee Shiong Lim, Tih-Shih Lee, Philip Yap, Keng Bee Yap, Tze Pin Ng (Handling Associate Editor: Kaarin Anstey)
Psychosocial Risk and Protective Factors and Incident Mild Cognitive Impairment and Dementia in Community Dwelling Elderly: Findings from the Singapore Longitudinal Ageing Study
Abstract: Background. Indicators of social isolation or support such as living alone, loneliness, being married, and life satisfaction are possible psychosocial risk and protective factors for dementia. Objective. We investigate the associations of these overlapping psychosocial factors with incident MCI-dementia (neurocognitive disorder) in a population cohort. Methods. Using data from 1601 participants of the Singapore Longitudinal Ageing Study (SLAS) who were free of MCI or dementia at baseline and followed up to 8 years, we estimated hazards ratio (HR) of association of living alone, loneliness, being married, and high life satisfaction with incident MCI-dementia. Results. In univariate analyses, individual HRs of association with incident MCI-dementia for living alone was 1.86 [1.18 – 2.95], (p=0.008), loneliness was 1.26 [0.86 -1.84], (p=0.23), being married was 0.54 [0.39 – 0.75] (p<0.0001), and being very satisfied with life was 0.59 [0.38–0.91]), (p=0.017). Adjusted mutually for other psychosocial variables, and for age, sex, education, ethnicity, smoking, alcohol, dyslipidemia, hypertension, diabetes, central obesity, history of stroke or heart disease, APOE-ε4, depression, physical, social, and productive activities, only being married (0.68 [0.47-0.99], p=0.044), and being very satisfied with life (0.61 [0.39 -0.96], p=0.034) remained significant variables associated with lower risks of developing MCI-dementia. Conclusion. Individuals who were married and those who were very satisfied with life are protected against the risk of developing MCI and dementia. Controlling for the adverse effects of being without spousal support and low life satisfaction, living alone or a feeling of loneliness were not associated with increased risk of MCI-dementia.

Pages 613-623
Jing Dong, Wei Qin, Cuibai Wei, Yi Tang, Qi Wang, Jianping Jia
A Novel PSEN1 K311R Mutation Discovered in Chinese Families with Late-Onset Alzheimer’s Disease Affects Amyloid-β Production and Tau Phosphorylation
Abstract: Background. Presenilin-1 (PSEN1) is the most frequently mutated gene in familial Alzheimer’s disease (AD), whereas only several novel mutations have been reported in China and functional studies were seldom conducted. Objective. We describe a novel PSEN1 K311R mutation in two Chinese families with late-onset AD and its functional impact on amyloid-β protein precursor (AβPP) processing and tau phosphorylation. Methods. The mutation was detected by direct sequencing of PSEN1 exon 9. HEK293 cells stably expressing wild-type APP695 (HEK293-APP695wt) were transfected with plasmids containing human wild-type PSEN1, PSEN1 K311R mutation, and PSEN1 E280A mutation to compare the K311R mutation’s effects on AβPP processing with other groups. In addition, each group of cells were co-transfected with plasmids harboring PSEN1 and human wild-type MAPT complementary DNA to study the mutation’s impacts on tau phosphorylation. Results. The K311R mutation was detected in probands of two late-onset AD families. Expression of the K311R or E280A mutation increased amyloid-β (Aβ)42 levels but decreased Aβ40 levels, resulting in an overall increase in the Aβ42/Aβ40 ratio compared to those in wild-type PSEN1 transfected cells (p<0.05). The K311R or E280A mutation also increased the levels of phosphorylated tau compared to wild-type PSEN1 (p<0.05). Conclusion. The K311R mutation might contribute to AD pathogenesis by overproducing toxic Aβ species and enhancing tau phosphorylation. Further in-depth studies are needed to decipher the pathogenic mechanisms of the K311R mutation in terms of AβPP cleavage, tau phosphorylation, and other presenilin-1 mediated functional pathways.

Pages 625-632
Carla Abdelnour, Octavio Rodríguez-Gómez, Montserrat Alegret, Sergi Valero, Sonia Moreno-Grau, Ángela Sanabria, Isabel Hernández, Maitee Rosende-Roca, Liliana Vargas, Ana Mauleón, Domingo Sánchez, Ana Espinosa, Gemma Ortega, Alba Pérez-Cordón, Susana Diego, Anna Gailhajanet, Marina Guitart, Óscar Sotolongo-Grau, Agustín Ruiz, Lluís Tárraga, Mercè Boada (Handling Associate Editor: Katie Gifford)
Impact of Recruitment Methods in Subjective Cognitive Decline
Abstract: Background: Recruitment methods can determine sample characteristics in mild cognitive impairment and Alzheimer’s disease dementia, but little is known about its influence in subjective cognitive decline (SCD). Objective: To determine the influence of two types of recruitment methods in the characteristics of individuals with SCD. Methods: We select and compare clinical and neuropsychological features, and frequency of APOE ε4 allele of 326 subjects with SCD from two cohorts: Open House Initiative (OHI) versus Memory Unit (MU). A logistic regression analysis (LRA), using gender and years of education as covariates, was used to examine the neuropsychological variables. Result: The OHI sample were mostly women (75.9% versus 64.5%, p<0.05), with higher educational level (12.15 [3.71] versus 10.70 [3.80] years, p=0.001), and more family history of dementia (138 [62.7%] versus 44 [41.5%], p<0.001) than the MU sample. Also, the OHI sample showed better overall neuropsychological performance than the MU sample, and after a LRA, this trend continued in automatic response inhibition capacity, abstract reasoning, and recognition memory. We did not find differences in age, depression history, and/or APOE ε4 allele frequency. Conclusion: SCD subjects showed different demographic and neuropsychological characteristics depending on the recruitment method, which should be taken into account in the design of research studies with this target population.

Pages 633-643
Miri Lutski, Galit Weinstein, Uri Goldbourt, David Tanne
Insulin Resistance and Future Cognitive Performance and Cognitive Decline in Elderly Patients with Cardiovascular Disease
Abstract: Background: The role of insulin resistance (IR) in the pathogenesis of cognitive performance is not yet clear. Objective: To examine the associations between IR and cognitive performance and change in cognitive functions two decades later in individuals with cardiovascular disease with and without diabetes. Methods: A subset of 489 surviving patients (mean age at baseline 58±6.6 y) with coronary heart disease who previously participated in the secondary prevention Bezafibrate Infarction Prevention (BIP trial; 1990-1997), were included in the current neurocognitive study. Biochemical parameters including IR (using the homeostasis model of assessment; HOMA-IR) were measured at baseline. During 2004-2008, computerized cognitive assessment and atherosclerosis parameters were measured (T1; n=558; mean age 72.6±6.4 years). A second cognitive assessment was performed during 2011-2013 (T2; n=351; mean age 77±6.4 years). Cognitive function, overall and in specific domains, was assessed. We used linear regression models and linear mixed models to evaluate the differences in cognitive performance and decline, respectively. Results: Controlling for potential confounders, IR (top HOMA-IR quartile versus others) was associated with subsequent poorer cognitive performance overall (β=-4.45± Standard Error (SE) 1.54; p=0.004) and on tests of memory and executive function among non-diabetic patients (β=-7.16±2.38; p=0.003 and β=-3.33±1.84; p=0.073, respectively). Moreover, among non-diabetic patients, IR was related to a greater decline overall (β=-0.17±0.06; p=0.008), and in memory (β=-0.22±0.10; p=0.024) and executive function (β=-0.19±0.08; p=0.012). The observed associations did not differ after excluding subjects with prevalent stroke or dementia. Conclusion: IR is related to subsequent poorer cognitive performance and greater cognitive decline among patients with cardiovascular disease.