Pages 325-327
Obituary
José Luna-Muñoz, George Perry, Jorge Guevara
Raul Mena: 1953-2014
Pages 329-347
Review
Paula Agostinho, Anna Pliássova, Catarina R. Oliveira, Rodrigo A. Cunha
Localization and Trafficking of Amyloid-β Protein Precursor and Secretases: Impact on Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) affects almost 35 million people worldwide. One of the neuropathological features of AD is the presence of extracellular amyloid plaques, which are mainly composed of amyloid-β (Aβ) peptides. These peptides derive from the amyloidogenic proteolytic processing of the amyloid-β protein precursor (AβPP), through the sequential action of β- and γ-secretases. However, AβPP can also be cleaved by a non-amyloidogenic pathway, involving an α-secretase, and in this case the Aβ formation is precluded. The production of Aβ and of other AβPP catabolites depends on the spatial and temporal co-localization of AβPP with α- or β-secretases and γ-secretase, which traffic through the secretory pathway in a highly regulated manner. Disturbances on AβPP and secretases intracellular trafficking and, consequently, in their localization may affect dynamic interactions between these proteins with consequences in the AD pathogenesis. In this article, we critically review the recent knowledge about the trafficking and co-localization AβPP and related secretases in the brain under physiological and AD conditions. A particular focus is given to data concerning the distribution of AβPP and secretases in different types of synapses relatively to other neuronal or glial localizations. Furthermore, we discuss some possible signals that govern the dynamic encounter of AβPP with each group of secretases, such as AβPP mutations, estrogen deprivation, chronic stress, metabolic impairment, and alterations in sleep pattern-associated with aging. The knowledge of key signals that are responsible for the shifting of AβPP processing away from α-secretases and toward the β-secretases might be useful to develop AD therapeutic strategies.
Pages 349-362
Hypothesis
Robert P. Friedland
Mechanisms of Molecular Mimicry Involving the Microbiota in Neurodegeneration
Abstract: The concept of molecular mimicry was established to explain commonalities of structure which developed in response to evolutionary pressures. Most examples of molecular mimicry in medicine have involved homologies of primary protein structure which cause disease. Molecular mimicry can be expanded beyond amino acid sequence to include microRNA and proteomic effects which are either pathogenic or salutogenic (beneficial) in regard to Parkinson’s disease, Alzheimer’s disease, and related disorders. Viruses of animal or plant origin may mimic nucleotide sequences of microRNAs and influence protein expression. Both Parkinson’s and Alzheimer’s diseases involve the formation of transmissible self-propagating prion-like proteins. However, the initiating factors responsible for creation of these misfolded nucleating factors are unknown. Amyloid patterns of protein folding are highly conserved through evolution and are widely distributed in the world. Similarities of tertiary protein structure may be involved in the creation of these prion-like agents through molecular mimicry. Cross-seeding of amyloid misfolding, altered proteostasis, and oxidative stress may be induced by amyloid proteins residing in bacteria in our microbiota in the gut and in the diet. Pathways of molecular mimicry induced processes induced by bacterial amyloid in neurodegeneration may involve TLR 2/1, CD14, and NFκB among others. Furthermore, priming of the innate immune system by the microbiota may enhance the inflammatory response to cerebral amyloids (such as amyloid-β and α-synuclein). This paper describes the specific molecular pathways of these cross-seeding and neuroinflammatory processes. Evolutionary conservation of proteins provides the opportunity for conserved sequences and structures to influence neurological disease through molecular mimicry.
Pages 363-367
Short Communication
Giorgio B. Boncoraglio*, Fabrizio Piazza*, Mario Savoiardo, Laura Farina, Jacopo C. DiFrancesco,Sara Prioni, Fabrizio Tagliavini, Eugenio A Parati, Giorgio Giaccone *These authors contributed equally to this work.
Prodromal Alzheimer’s Disease Presenting as Cerebral Amyloid Angiopathy-Related Inflammation with Spontaneous Amyloid-Related Imaging Abnormalities and High Cerebrospinal Fluid Anti-Aβ Autoantibodies
Abstract: Cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare form of vasculitis associated with amyloid-β (Aβ) deposition in vessel walls, has been proposed as a spontaneous human model of the amyloid-related imaging abnormalities (ARIA) occurring after anti-Aβ immunotherapy for the treatment of Alzheimer’s disease (AD). We describe a case of a patient with biopsy-proven CAA-ri and prodromal AD, confirmed by means of neuropsychological examination after 20 months follow-up, presenting with ARIA and high levels of cerebrospinal fluid anti-Aβ autoantibodies. This case further supports the analogies between the inflammatory response driven by anti-Aβ immunotherapy and that spontaneously occurring in CAA-ri.
Pages 369-372
Short Communication
Michael A. Williams, David Haughton, Michael Stevenson, David Craig, A. Peter Passmore, Giuliana Silvestri
Plasma Complement factor H in Alzheimer’s Disease
Abstract: Biomarkers for Alzheimer’s disease (AD) should meet several criteria, including simplicity of testing. Inappropriate activation of the complement cascade has been implicated in the pathogenesis of AD. Complement factor H (CFH) is a regulator of the cascade, but studies on plasma CFH levels in AD have provided mixed results. This study compared plasma CFH levels in 317 AD cases with 254 controls using an immunodiffusion assay. The sample had an 80% power to detect a difference of 23 mg/L between cases and controls, but no difference was evident. Plasma CFH may not be a suitable biomarker for AD.
Pages 373-386
Qin Xia, Hongfeng Wang, Yan Zhang, Zheng Ying, Guanghui Wang (Handling Associate Editor: Ling-Qiang Zhu)
Loss of TDP-43 Inhibits Amyotrophic Lateral Sclerosis-Linked Mutant SOD1 Aggresome Formation in an HDAC6-Dependent Manner
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, and progressive neurodegenerative disorder with no cure. Cu/Zn-superoxide dismutase (SOD1) was the first identified protein associated with familial ALS; and aggresome formation of misfolded SOD1 is closely associated with ALS pathogenesis. HDAC6, one of the histone deacetylase family members, has already been demonstrated to play an important role in regulating aggresome formation of misfolded proteins and protecting cells against the toxicity induced by misfolded proteins. In this study, we found that in a cellular model with impaired proteasome activity, the TAR DNA-binding protein 43, which is closely linked with ALS and associated with various neurodegenerative disorders such as frontotemporal lobar degeneration, Alzheimer’s disease, and Parkinson’s disease, can regulate mutant SOD1 aggresome formation through an HDAC6-dependent manner. TDP-43 deficiency did not affect poly-ubiquitination of mutant SOD1, whereas it greatly decreased the expression level of HDAC6, which is required for aggresome formation of ALS-linked mutant SOD1. Moreover, overexpression of siRNA-resistant HDAC6 restored mutant SOD1 aggresome formation in TDP-43-knockdown cells. Thus, our data provide evidence that TDP-43 plays an important role in mutant SOD1 aggresome formation through its regulation of HDAC6.
Pages 387-394
Simona Lattanzi, Simona Luzzi, Leandro Provinciali, Mauro Silvestrini (Handling Associate Editor: Jack de la Torre)
Blood Pressure Variability in Alzheimer’s Disease and Frontotemporal Dementia: The Effect on the Rate of Cognitive Decline
Abstract: Background: The link between vascular disease and cognitive impairment is a matter of an ongoing debate, and different cardiovascular conditions have been found to be predictors of the clinical development and progression of cognitive dysfunction. Objective: To compare the influence of visit-to visit blood pressure (BP) variability on the rate of cognitive decline in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Methods: The patients affected by AD and FTD consecutively admitted to our center from January 2007 to September 2012 were evaluated every three months for a one-year period. The BP mean and coefficient of variation as index of variability were obtained for both systolic and diastolic values. Progression of cognitive decline was investigated using the Mini-Mental State Examination administered at entry and at the end of the follow-up. Results: Two-hundred and forty-eight AD and eighty-one FTD patients were enrolled. Systolic and diastolic BP mean and variability were comparable between the two groups. Systolic BP variability (BPV) was associated with the rate of cognitive impairment in AD (B=0.367, beta=0.739, R2=0.594, adjusted R2=0.567; p<0.001), but not in FTD patients; no relationship emerged between any other BP index and cognitive decline. Conclusion: The relationship between BPV and cognitive function is still not completely understood, and it may play different roles according to the types and stages of dementia. Fluctuations in systolic BP may contribute to the cognitive decline in AD patients and may represent a neglected therapeutic target.
Pages 395-405
Ruth Remington, Cynthia Bechtel*, David Larsen*, Annmarie Samar*, Laura Doshanjh, Paul Fishman, Yuan Luo, Kathleen Smyers, Robert Page, Christopher Morrell, Thomas B. Shea *These authors, listed in alphabetical order, contributed equally to this study.
A Phase II Randomized Clinical Trial of a Nutritional Formulation for Cognition and Mood in Alzheimer’s Disease
Abstract: Background: Increasing evidence points toward the efficacy of nutritional modifications in delaying cognitive decline and mood/behavioral difficulties in Alzheimer’s disease (AD). Nutritional supplementation with individual agents has shown varied results suggesting the need for combinatorial intervention. Objective: We set out to determine whether nutritional intervention could positively impact cognitive performance and behavioral difficulties for individuals diagnosed with AD. Methods: A double-blind, multi-site, phase II study (ClinicalTrials.gov NCT01320527; Alzheimer’s Association Trialmatch) was conducted in which 106 individuals with AD were randomized to a nutraceutical formulation (NF; folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) or placebo for 3 or 6 months, followed by an open-label extension where participants received NF for 6 additional months. Results: The NF cohort improved versus the placebo cohort within 3 months (Clox-1 p = 0.0083, 95%CI [0.4481, 2.9343]; Dementia Rating Scale p = 0.0266, 95%CI [0.1722, 2.7171]). Caregivers reported non-significant improvements in Neuropsychiatric Inventory. Both cohorts improved or maintained baseline performance during open-label extensions. Activities of Daily Living did not change for either cohort. Conclusions: These findings extend phase I studies where NF maintained or improved cognitive performance and mood/behavior.
Pages 407-421
Mercedes Armand-Ugón, Ester Aso, Jesús Moreno, Miquel Riera-Codina, Alex Sánchez, Esteban Vegas, Isidre Ferrer (Handling Associate Editor: Gemma Casadesus)
Memory Improvement in the AβPP/PS1 Mouse Model of Familial Alzheimer’s Disease Induced by Carbamylated-Erythropoietin is Accompanied by Modulation of Synaptic Genes
Abstract: Neuroprotection of erythropoietin (EPO) following long-term administration is hampered by the associated undesirable effects on hematopoiesis and body weight. For this reason, we tested carbamylated-EPO (CEPO), which has no effect on erythropoiesis, and compared it with EPO in the AβPP/PS1 mouse model of familial Alzheimer’s disease. Groups of 5-month-old wild type (WT) and transgenic mice received chronic treatment consisting of CEPO (2,500 or 5,000 UI/kg) or EPO (2,500 UI/kg) 3 days/week for 4 weeks. Memory at the end of treatment was assessed with the object recognition test. Microarray analysis and quantitative-PCR were used for gene expression studies. No alterations in erythropoiesis were observed in CEPO-treated WT and AβPP/PS1 transgenic mice. EPO and CEPO improved memory in AβPP/PS1 animals. However, only EPO decreased amyloid-β (Aβ) plaque burden and soluble Aβ40. Microarray analysis of gene expression revealed a limited number of common genes modulated by EPO and CEPO. CEPO but not EPO significantly increased gene expression of dopamine receptors 1 and 2, and adenosine receptor 2a, and significantly down-regulated adrenergic receptor α1D and gastrin releasing peptide. CEPO treatment resulted in higher protein levels of dopamine receptors 1 and 2 in WT and AβPP/PS1 animals, whereas the adenosine receptor 2a was reduced in WT animals. The present results suggest that the improved behavior observed in AβPP/PS1 transgenic mice after CEPO treatment may be mediated, at least in part, by the observed modulation of the expression of molecules involved in neurotransmission.
Pages 423-435
Xiaochuan Wang*, Julie Blanchard*, Yunn Chyn Tung, Inge Grundke-Iqbal, Khalid Iqbal (Handling Associate Editor: Michal Novak) *These authors contributed equally to this work.
Inhibition of Protein Phosphatase-2A (PP2A) by I1PP2A Leads to Hyperphosphorylation of Tau, Neurodegeneration, and Cognitive Impairment in Rats
Abstract: Protein phosphatase-2A (PP2A) deficiency is a cause of the abnormal hyperphosphorylation of tau, which composes neurofibrillary tangles (NFTs) in Alzheimer’s disease (AD) brain. We previously reported that both mRNA and protein expression of inhibitor I of PP2A (I1PP2A) are elevated in AD brain and that this inhibitor induces a dose-dependent inhibition of PP2A activity and tau hyperphosphorylation in NIH3T3 cells. However, whether I1PP2A can induce AD neurofibrillary degeneration and cognitive impairment was not known. In the present study, we infected the brains of rat pups within 24 hours of birth with adeno-associated virus serotype 1 (AAV1) carrying I1PP2A. In the adult AAV1-I1PP2A rats, we found a decrease in PP2A activity and abnormal hyperphosphorylation of tau in the brain. Immunohistochemistry showed a significant reduction of MAP2 and synapsin 1 in AAV1- I1PP2A animals, suggesting that I1PP2A can induce a loss of dendritic and synaptic plasticity markers. Behavioral tests revealed that infection with AAV1- I1PP2A induced deficits in exploratory activity, spatial reference memory, and memory consolidation in adult rats. These studies suggest that I1PP2A can inhibit PP2A activity, and in turn induce AD neurofibrillary degeneration and cognitive deficits in rats.
Pages 437-447
Roger Pamphlett, Stephen Kum Jew (Handling Associate Editor: Irina Alafuzoff)
Different Populations of Human Locus Ceruleus Neurons Contain Heavy Metals or Hyperphosphorylated Tau: Implications for Amyloid-β and Tau Pathology in Alzheimer’s Disease
Abstract: A marked loss of locus ceruleus (LC) neurons is a striking pathological feature of Alzheimer’s disease (AD). LC neurons are particularly prone to taking up circulating toxicants such as heavy metals, and hyperphosphorylated tau (tauHYP) appears early in these neurons. In an attempt to find out if both heavy metals and tauHYP could be damaging LC neurons, we looked in the LC neurons of 21 sporadic AD patients and 43 non-demented controls for the heavy metals mercury, bismuth, and silver using autometallography, and for tauHYP using AT8 immunostaining. Heavy metals or tauHYP were usually seen in separate LC neurons, and rarely co-existed within the same neuron. The number of heavy metal-containing LC neurons did not correlate with the number containing tauHYP. Heavy metals therefore appear to occupy mostly different population of LC neurons to those containing tauHYP, indicating that the LC in AD is vulnerable to two different assaults. Reduced brain noradrenaline from LC damage is linked to amyloid-β deposition, and tauHYP in the LC may seed neurofibrillary tangles in other neurons. A model is described, incorporating the present findings, that proposes that the LC plays a part in both the amyloid-β and tau pathologies of AD.
Pages 449-456
Edina Varga, Gábor Juhász, Zsolt Bozsó, Botond Penke, Lívia Fülöp, Viktor Szegedi
Amyloid-β1-42 Disrupts Synaptic Plasticity by Altering Glutamate Recycling at the Synapse
Abstract: Alzheimer’s disease (AD) is the most prevalent form of neurodegenerative disorders characterized by neuritic plaques containing amyloid-β peptide (Aβ) and neurofibrillary tangles. Evidence has been reported that Aβ1-42 plays an essential pathogenic role in decreased spine density, impairment of synaptic plasticity, and neuronal loss with disruption of memory-related synapse function, all associated with AD. Experimentally, Aβ1-42 oligomers perturb hippocampal long-term potentiation (LTP), an electrophysiological correlate of learning and memory. Aβ was also reported to perturb synaptic glutamate (Glu)-recycling by inhibiting excitatory-amino-acid-transporters. Elevated level of extracellular Glu leads to activation of perisynaptic receptors, including NR2B subunit containing NMDARs. These receptors were shown to induce impaired LTP and enhanced long-term depression and proapoptotic pathways, all central features of AD. In the present study, we investigated the role of Glu-recycling on Aβ1-42-induced LTP deficit in the CA1. We found that Aβ-induced LTP damage, which was mimicked by the Glu-reuptake inhibitor TBOA, could be rescued by blocking the NR2B subunit of NMDA receptors. Furthermore, decreasing the level of extracellular Glu using a Glu scavenger also restores TBOA or Aβ induces LTP damage. Overall, these results suggest that reducing ambient Glu in the brain can be protective against Aβ-induced synaptic disruption.
Pages 457-470
Simona Gardini, Annalena Venneri, Fabio Sambataro, Fernando Cuetos, Fabrizio Fasano, Massimo Marchi, Girolamo Crisi, Paolo Caffarra
Increased Functional Connectivity in the Default Mode Network in Mild Cognitive Impairment: A Maladaptive Compensatory Mechanism Associated with Poor Semantic Memory Performance
Abstract: Semantic memory decline and changes of default mode network (DMN) connectivity have been reported in mild cognitive impairment (MCI). Only a few studies, however, have investigated the role of changes of activity in the DMN on semantic memory in this clinical condition. The present study aimed to investigate more extensively the relationship between semantic memory impairment and DMN intrinsic connectivity in MCI. Twenty-one MCI patients and 21 healthy elderly controls matched for demographic variables took part in this study. All participants underwent a comprehensive semantic battery including tasks of category fluency, visual naming and naming from definition for objects, actions and famous people, word-association for early and late acquired words and reading. A subgroup of the original sample (16 MCI patients and 20 healthy elderly controls) was also scanned with resting state functional magnetic resonance imaging and DMN connectivity was estimated using a seed-based approach. Compared with healthy elderly, patients showed an extensive semantic memory decline in category fluency, visual naming, naming from definition, words-association, and reading tasks. Patients presented increased DMN connectivity between the medial prefrontal regions and the posterior cingulate and between the posterior cingulate and the parahippocampus and anterior hippocampus. MCI patients also showed a significant negative correlation of medial prefrontal gyrus connectivity with parahippocampus and posterior hippocampus and visual naming performance. Our findings suggest that increasing DMN connectivity may contribute to semantic memory deficits in MCI, specifically in visual naming. Increased DMN connectivity with posterior cingulate and medio-temporal regions seems to represent a maladaptive reorganization of brain functions in MCI, which detrimentally contributes to cognitive impairment in this clinical population.
Pages 471-482
Julius N. Meißner, Yvonne Bouter, Thomas A. Bayer
Neuron Loss and Behavioral Deficits in the TBA42 Mouse Model Expressing N-Truncated Pyroglutamate Amyloid-β3-42
Abstract: Pyroglutamate-modified amyloid-β (Aβ) at amino acid position three (AβpE3-42) is gaining considerable attention as a potential key player in the pathogenesis of Alzheimer’s disease (AD). AβpE3-42 is abundant in AD brain and has a high aggregation propensity, stability, and cellular toxicity. The aim of the present work was to study the effect of AβpE3-42 expression on neuron loss and associated behavioral deficits using the TBA42 transgenic mouse model. Pyroglutamate Aβ is an abundant, toxic peptide in AD brain. Expression of pyroglutamate Aβ3-42 triggers hippocampal CA1 neuron loss and behavioral deficits in the TBA42 mouse model. Mice elicited significant neuron death (-35% at the age of 12 months), deficits in the spatial reference memory, working memory, loss of anxiety, and severe motor deficits in an age-dependent manner. These results support a major pathological function of pyroglutamate Aβ in AD.
Pages 483-494
Maria Caterina Silveri, Ilaria Ferrante, Anna Clelia Brita, Paola Rossi, Rosa Liperoti, Federica Mammarella, Roberto Bernabei, Maria Vittoria Marini Chiarelli, Martina De Luca (Handling Associate Editor: Allyson Rosen)
“The Memory of Beauty” Survives Alzheimer’s Disease (but Cannot Help Memory)
Abstract: The aesthetic experience, in particular the experience of beauty in the visual arts, should have neural correlates in the human brain. Neuroesthetics is principally implemented by functional studies in normal subjects, but the neuropsychology of the aesthetic experience, that is, the impact of brain damage on the appreciation of works of art, is a neglected field. Here, 16 mild to moderate Alzheimer’s disease patients and 15 caregivers expressed their preference on 16 works of art (eight representational and eight abstract) during programmed visits to an art gallery. A week later, all subjects expressed a preference rate on reproductions of the same works presented in the gallery. Both patients and caregivers were consistent in assigning preference ratings, and in patients consistency was independent of the ability to recognize the works on which the preference rate had been given in an explicit memory task. Caregivers performed at ceiling in the memory task. Both patients and caregivers assigned higher preference ratings for representational than for abstract works and preference consistency was comparable in representational and abstract works. Furthermore, in the memory task, patients did not recognize better artworks they had assigned higher preference ratings to, suggesting that emotional stimuli (as presumably visual works of art are) cannot enhance declarative memory in this pathology. Our data, which were gathered in an ecological context and with real-world stimuli, confirm previous findings on the stability of aesthetic preference in patients with Alzheimer’s disease and on the independence of aesthetic preference from cognitive abilities such as memory.
Pages 495-507
Joana M. Oliveira, Ana Gabriela Henriques, Filipa Martins, Sandra Rebelo, Odete A.B. da Cruz e Silva
Amyloid-β Modulates Both AβPP and Tau Phosphorylation
Abstract: Two histopathological hallmarks of Alzheimer’s disease (AD), the tau rich neurofibrillary tangles and the senile plaques, predominating in amyloid-β (Aβ), have fueled research in distinct directions. Evidence suggests that Aβ triggers imbalanced activities of protein phosphatases and kinases thus affecting the phosphorylation state of tau in AD. The amyloid-β protein precursor (AβPP) itself appears to be hyperphosphorylated at different residues in AD brains, including at Thr668. The results reported in this manuscript show, for the first time, that Aβ42 can impact upon the AβPP phosphorylation state at the Thr668 residue. This novel finding supports a putative model, whereby Aβ can modulate the phosphorylation state of AβPP regulating its processing and consequently its own production. Furthermore, the data presented shows that in primary cortical neurons, GSK3β and Cdk5 are involved in AβPP phosphorylation at this residue and that PP1 and PP2B participate in AβPP dephosphorylation. Consistent with other reports, Aβ was capable of increasing tau phosphorylation at the Ser396 and Ser262 residues. This peptide is therefore a strong candidate for promoting the cross talk between signaling pathways, which simultaneously result in AβPP and tau hyperphosphorylation. In closing, the Aβ effect on protein kinases and protein phosphatases may constitute an alternative mechanism by which the peptide is able to modulate the phosphorylation state of both AβPP and tau in AD.
Pages 509-520
Kole D. Meeker, James S. Meabon, David G. Cook
Partial Loss of the Glutamate Transporter GLT-1 Alters Brain Akt and Insulin Signaling in a Mouse Model of Alzheimer’s Disease
Abstract: The glutamate transporter GLT-1 (also called EAAT2 in humans) plays a critical role in regulating extracellular glutamate levels in the central nervous system (CNS). In Alzheimer’s disease (AD), EAAT2 loss is associated with neuropathology and cognitive impairment. In keeping with this, we have reported that partial GLT-1 loss (GLT-1+/-) causes early-occurring cognitive deficits in mice harboring familial AD AβPPswe/PS1ΔE9 mutations. GLT-1 plays important roles in several molecular pathways that regulate brain metabolism, including Akt and insulin signaling in astrocytes. Significantly, AD pathogenesis also involves chronic Akt activation and reduced insulin signaling in the CNS. In this report we tested the hypothesis that GLT-1 heterozygosity (which reduces GLT-1 to levels that are comparable to losses in AD patients) in AβPPswe/PS1ΔE9 mice would induce sustained activation of Akt and disturb components of the CNS insulin signaling cascade. We found that partial GLT-1 loss chronically increased Akt activation (reflected by increased phosphorylation at serine 473), impaired insulin signaling (reflected by decreased IRβ phosphorylation of tyrosines 1150/1151 and increased IRS-1 phosphorylation at serines 632/635 – denoted as 636/639 in humans), and reduced insulin degrading enzyme (IDE) activity in brains of mice expressing familial AβPPswe/PS1DE9 AD mutations. GLT-1 loss also caused an apparent compensatory increase in IDE activity in the liver, an organ that has been shown to regulate peripheral amyloid-β levels and expresses GLT-1. Taken together, these findings demonstrate that partial GLT-1 loss can cause insulin/Akt signaling abnormalities that are in keeping with those observed in AD.
Pages 521-526
Benjamin Cretin, Laure Di Bitonto, Frederic Blanc, Eloi Magnin
Left Temporal Lobe Epilepsy Revealing Left Posterior Cortical Atrophy Due to Alzheimer’s Disease
Abstract: Seizures can be an early symptom of Alzheimer’s disease (AD) and can precede cognitive decline. Early epilepsy in AD can mimic transient epileptic amnesic syndrome (TEAS) or epileptic amnesic syndrome. We report the case of a patient who started a cerebrospinal fluid (CSF)-proven AD with partial seizures and TEAS that secondarily became a cortical posterior atrophy syndrome. CSF biomarkers showed a high amyloid production, amyloidopathy, and high level of total tau and p-Tau. This observation adds data to the complex AD-early epilepsy interactions and illustrates that atypical AD can cause a TEAS. Possible red flags for an underlying neurodegenerative process in TEAS are discussed.
Pages 527-542
D. Richard Lachno, Barbara A. Evert, Kaia Maloney, Brian A. Willis, Jayne A. Talbot, Manu Vandijck, Robert A. Dean (Handling Associate Editor: Henrik Zetterberg)
Validation and Clinical Utility of ELISA Methods for Quantification of Amyloid-β Peptides in Cerebrospinal Fluid Specimens from Alzheimer’s Disease Studies
Abstract: The aim of this study was to validate assays for measurement of amyloid-β (Aβ) peptides in cerebrospinal fluid (CSF) specimens according to regulatory guidance and demonstrate their utility with measurements in specimens from Alzheimer’s disease (AD) studies. Methods based on INNOTEST® β-AMYLOID(1-42) and prototype INNOTEST® β-AMYLOID(1-40) ELISA kits were developed involving pre-analytical sample treatment with Tween-20 for reliable analyte recovery. Validation parameters were evaluated by repeated testing of CSF pools collected and stored in the same manner as clinical specimens. Intra- and inter-assay coefficients of variation were ≤11% and relative accuracy was within ±10% for both analytes. Dilutional linearity was demonstrated for both analytes from a spiked CSF pool, but not from a non spiked native CSF pool. Recovery of standard Aβ peptide spikes ranged from 77% to 93%. No interference was observed from the investigational drugs LY2811376, LY2886721, LY3002813, or semagacestat. Aβ1-40 and Aβ1-42 were stable in CSF for up to 8 hours at room temperature and during 5 freeze-thaw cycles from ≤−20°C and ≤−70°C. In frozen native CSF specimens, Aβ1-40 was mostly stable up to 3 years at ≤−70°C, whereas stability of Aβ1-42 was limited to 221 days. Dose-dependent changes in measured CSF Aβ were observed in healthy volunteers up to 36 hours after treatment with the β-site cleavage enzyme inhibitor LY2886721. In conclusion, rigorous validation tests have successfully demonstrated the strengths and operational limitations of these INNOTEST®-based assays. They have proved to be robust and reliable tools for pharmacodynamic evaluations of investigational AD therapeutics in clinical trials.
Pages 543-552
Kengo Ito, Hidenao Fukuyama, Michio Senda, Kazunari Ishii, Kiyoshi Maeda, Yasuji Yamamoto, Yasuomi Ouchi, Kenji Ishii, Ayumu Okumura, Ken Fujiwara, Takashi Kato, Yutaka Arahata, Yukihiko Washimi, Yoshio Mitsuyama, Kenichi Meguro, Mitsuru Ikeda, SEAD-J Study Group (Handling Associate Editor: Henryk Barthel)
Prediction of Outcomes in Mild Cognitive Impairment by Using 18F-FDG-PET: A Multicenter Study
Abstract: Background: 18F-FDG-PET is defined as a biomarker of neuronal injury according to the revised National Institute on Aging–Alzheimer’s Association criteria. Objective: The objective of this multicenter prospective cohort study was to examine the value of 18F-FDG-PET in predicting the development of Alzheimer’s disease (AD) in patients with mild cognitive impairment (MCI). Methods: In total, 114 patients with MCI at 9 participating institutions underwent clinical and neuropsychological examinations, MRI, and 18F-FDG-PET at baseline. The cases were visually classified into predefined dementia patterns by three experts. An automated analysis for 18F-FDG-PET was also performed to calculate the PET score. Subjects were followed periodically for 3 years, and progression to dementia was evaluated. Results: In 47% of the patients with MCI, progression of symptoms justified the clinical diagnosis of “probable AD”. The PET visual interpretation predicted conversion to AD during 3-year follow-up with an overall diagnostic accuracy of 68%. Overall diagnostic accuracy of the PET score was better than that of PET visual interpretation at all follow-up intervals, and the optimized PET score threshold revealed the best performance at the 2-year follow-up interval with an overall diagnostic accuracy of 83%, a sensitivity of 70%, and a specificity of 90%. Multivariate logistic regression analysis identified the PET score as the most significant predictive factor distinguishing AD converters from non-converters. Conclusion: The PET score is the most statistically significant predictive factor for conversion from MCI to AD, and the diagnostic performance of the PET score is more promising for rapid converters over 2 years.
Pages 553-560
Frédéric Revel, Thomas Gilbert, Sylvain Roche, Jocelyne Drai, Emilie Blond, René Ecochard, Marc Bonnefoy
Influence of Oxidative Stress Biomarkers on Cognitive Decline
Abstract: Background: Abnormal oxidative stress is an established feature of Alzheimer’s disease (AD). Markers of lipoperoxidation and deficits in serum antioxidants could have a predictive value for identifying subjects at risk of dementia and to predict cognitive decline. Objective: Search for relationships between the levels of some oxidative stress biomarkers and cognitive function decline that would help predict this decline. Methods: The study solicited and included 97 patients aged 63 to 93 years with various suspected neurodegenerative diseases (35 with AD). They were followed up at six-month intervals over two years (2010-2012). The study: i) assessed the blood levels of glutathione peroxidase, glutathione, and malondialdehyde; ii) performed the Mini-Mental Status Examination (MMSE), the Clock Drawing test, the free/cued recall task with 16-item lists, and the cue percentage; the Trail Making Test; and iii) acquired brain magnetic resonance imaging or tomodensitometry. The primary outcome measure was the MMSE score. Results: The MMSE score was correlated with the score of each neuropsychological test, the age at baseline, and the glutathione level. On average, the decline in the MMSE score was 1.63 points per six months. A 100 International Unit increase in glutathione peroxidase was associated with an average loss of 1.19 MMSE points per six months (p=0.002). A 100 µmol/L increase in glutathione was associated with an average loss of 1.80 MMSE points per six months (p=0.014). Conclusion: Oxidative stress biomarkers, especially glutathione peroxidase and glutathione, may predict the course of cognitive decline in patients with AD or other neurodegenerative disorders.
Pages 561-580
Hua Zhang, Jie Liu, Suya Sun, Ekaterina Pchitskaya, Elena Popugaeva, Ilya Bezprozvanny
Calcium Signaling, Excitability, and Synaptic Plasticity Defects in Mouse Model of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) and aging result in impaired ability to store memories, but the cellular mechanisms responsible for these defects are poorly understood. Presenilin 1 (PS1) mutations are responsible for many early-onset familial AD (FAD) cases. The phenomenon of hippocampal long-term potentiation (LTP) is widely used in studies of memory formation and storage. Recent data revealed long-term LTP maintenance (L-LTP) is impaired in PS1-M146V knock-in (KI) FAD mice. To understand the basis for this phenomenon, in the present study we analyzed structural synaptic plasticity in hippocampal cultures from wild type (WT) and KI mice. We discovered that exposure to picrotoxin induces formation of mushroom spines in both WT and KI cultures, but the maintenance of mushroom spines is impaired in KI neurons. This maintenance defect can be explained by an abnormal firing pattern during the consolidation phase of structural plasticity in KI neurons. Reduced frequency of neuronal firing in KI neurons is caused by enhanced calcium-induced calcium release (CICR), enhanced activity of calcium-activated potassium channels, and increased afterhyperpolarization. As a result, “consolidation” pattern of neuronal activity converted to “depotentiation” pattern of neuronal activity in KI neurons. Consistent with this model, we demonstrated that pharmacological inhibitors of CICR (dantrolene), of calcium-activated potassium channels (apamin), and of calcium-dependent phosphatase calcineurin (FK506) are able to rescue structural plasticity defects in KI neurons. Furthermore, we demonstrate that incubation with dantrolene or apamin also rescued L-LTP defects in KI hippocampal slices, suggesting a role for a similar mechanism. This proposed mechanism may be responsible for memory defects in AD but also for age-related memory decline.
Pages 581-597
Noémie Moreau, Stéphane Rauzy, Bernadette Bonnefoi, Laurent Renié, Laurent Martinez-Almoyna, François Viallet, Maud Champagne-Lavau
Different Patterns of Theory of Mind Impairment in Mild Cognitive Impairment
Abstract: Theory of Mind refers to the ability to infer other’s mental states, their beliefs, intentions, or knowledge. To date, only two studies have reported the presence of Theory of Mind impairment in mild cognitive impairment (MCI). In the present study, we evaluated 20 MCI patients and compared them with 25 healthy control participants using two Theory of Mind tasks. The first task was a false belief paradigm as frequently used in literature, and the second one was a referential communication task, assessing Theory of Mind in a real situation of interaction and which had never been used before in this population. The results showed that MCI patients presented difficulties inferring another person’s beliefs about reality and attributing knowledge to them in a situation of real-life interaction. Two different patterns of Theory of Mind emerged among the patients. In comparison with the control group, some MCI patients demonstrated impairment only in the interaction task and presented isolated episodic memory impairment, while others were impaired in both Theory of Mind tasks and presented cognitive impairment impacting both episodic memory and executive functioning. Theory of Mind is thus altered in the very early stages of cognitive impairment even in real social interaction, which could impact precociously relationships in daily life.
Pages 599-608
Byoung Seok Ye, Seong Hye Choi, Seol-Heui Han, SangYun Kim, Dong-Won Yang, Kee Hyung Park, Hyun Jeong Han, Young Chul Youn, Byung-Ok Choi, Seung H. Kim, Sook-young Woo, Duk L. Na, Eun-Joo Kim (Handling Associate Editor: John Hodges)
Clinical and Neuropsychological Comparisons of Early-Onset versus Late-Onset Frontotemporal Dementia: A CREDOS FTD Study
Abstract: Background: Cognitive performance changes with chronological aging. Previous studies investigating clinical heterogeneity in frontotemporal dementia (FTD) according to the age of symptom onset did not consider the effect of chronological aging on cognition. Objective: We compared cognitive and behavioral symptoms in patients with early-onset (EO) and late-onset (LO) FTD with consideration of chronological aging effect. Methods: A total of 166 FTD patients were enrolled consecutively from multi-center memory clinics using a nationwide FTD register. To control for the effects of chronological aging on neuropsychological scores, seven hundred and two subjects with normal cognition were also enrolled and regression models were set up. Neuropsychological scores that were detrended with the regression models and the behavioral symptoms of the EO-FTD and LO-FTD groups were compared. Subgroup analyses were performed for three main subtypes of FTD, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA). Results: Among 166 FTD patients, there were 76 bvFTD, 57 SD, and 33 PNFA patients who met new diagnostic criteria for bvFTD or primary progressive aphasia, respectively. LO-FTD (48.2%) was more common than previously thought and the proportions of EO and LO groups differed across FTD subtypes. EO-FTD patients had lower memory and frontal/executive scores and more prominent frontal/behavioral symptoms than LO-FTD patients. Conclusion: Our study suggested that FTD could be heterogeneous with respect the age of symptom onset. After controlling for the effects of chronological aging, EO-FTD patients exhibited more profound memory and frontal/executive dysfunction and more behavioral symptoms than LO-FTD patients.
Pages 609-620
Luís F.J.R. Miranda, Karina B. Gomes, Josianne N. Silveira, Gerson A. Pianetti, Ricardo M.D. Byrro, Patrícia R.H. Peles, Fernando H. Pereira, Thiago R. Santos, Arthur G. Assini, Valéria V. Ribeiro, Pedro A.L. Tito, Rafael O. Matoso, Thiago O.L. Lima, Edgar N. Moraes, Paulo Caramelli (Handling Associate Editor: Ricardo Allegri)
Predictive Factors of Clinical Response to Cholinesterase Inhibitors in Mild and Moderate Alzheimer’s Disease and Mixed Dementia: A One-Year Naturalistic Study
Abstract: Background: Naturalistic studies evaluate individuals in their usual way of living, presenting more “real-life” data regarding patients and their diseases. Objective: To investigate demographic, clinical, and genetic factors that could be predictive of good response to cholinesterase inhibitors (ChEI) treatment in Alzheimer’s disease (AD) and AD + cerebrovascular disease (CVD). Patients and Methods: A total of 129 patients were diagnosed with AD or AD + CVD and with mild-to-moderate dementia. After a 12-month treatment, 97 patients completed the study. They were evaluated at baseline and after three, six, and 12 months of ChEI (donepezil or rivastigmine or galantamine) use. APOE genotype and CYP2D6 polymorphisms were determined for all of the participants. In each visit, we used cognitive, functional, mood, and behavior scales. We classified patients according to their scores in the Mini-Mental State Examination (MMSE). Good responders were defined as those scoring ≥ 2 in the MMSE at 12 months. Results: The rate of good clinical response was 27.8%. In a longitudinal analysis, the patients with mild AD and also good responders at three months were considered to be good responders at 12 months. There was no correlation between ChEI dose, APOE and CYP2D6 polymorphisms, and the pattern of clinical response. Conclusion: A higher rate of good response was observed in this study compared to that in previous investigations. The pharmacogenetic aspects do not seem to have an influence in the response.
Pages 621-629
Sonia Moreno-Grau, Bruna Barneda, Paulina Carriba, Juan Marín, Oscar Sotolongo-Grau, Isabel Hernández, Maitée Rosende-Roca, Ana Mauleón, Liliana Vargas, Ana Espinosa, Montserrat Alegret, Octavio Rodriguez, Gemma Ortega, Maria Victoria Fernández, Jesús López-Arrieta, Lluís Tárraga, Mercè Boada, Carmen Antúnez, Joaquin López, Agustín Ruiz, Joan Xavier Comella (Handling Associate Editor: Benedetta Nacmias)
Evaluation of Candidate Genes Related to Neuronal Apoptosis in Late-Onset Alzheimer’s Disease
Abstract: The objective of this study was to identify genetic variation in genes encoding death receptors and signals that modulate their activity. After conducting a meta-analysis with five previous genome-wide association studies and aggregated data, the most significant signals, (TNF locus: rs2395488, rs2534672, and rs9267445; and FASLG locus: rs730278), were replicated in 1,046 cases and 372 controls. The rs2395488 and rs2534672 markers showed a modest protective effect (OR = 0.849, p = 0.49780; OR = 0.687, p = 0.11335), in contrast to rs730278 marker (OR = 1.146, p = 0.17212), which did not follow the previous effect direction; in any case it reached the significance level. Final meta-analysis, adding the replication sample, confirmed these observations. We concluded that FASLG marker is not etiologically linked to Alzheimer’s disease. However, single nucleotide polymorphisms around TNF locus require further analyses in order to explain the association between Alzheimer’s disease and human leukocyte antigen.
Pages 631-638
Evelyne Moyse, Christine Bastin, Eric Salmon, Serge Brédart (Handling Associate Editor: Hanna Chainay)
Impairment of Age Estimation from Faces in Alzheimer’s Disease
Abstract: A prerequisite for any function in social cognition is the perception and processing of social cues. Age estimation is a skill that is used in everyday life and is fundamental in social interactions. This study evaluated whether facial age estimation is impaired in patients with mild to moderate Alzheimer’s disease (AD). The current age of faces is known to have an impact on age estimation, and therefore stimuli belonging to different age groups (young, middle-aged, and older adults’ faces) were used. As expected, an impairment of age estimation from faces was observed in mild to moderate AD patients. However, the profile of impairment depended on the age of faces and stage of the disease. Mild AD patients presented difficulties mainly in assessing the age of middle-aged adults. In moderate disease stage, these difficulties also affected the age estimation of young adult faces. Interestingly, AD patients remained relatively good at estimating the age of older adults’ faces, compared to healthy controls.
Pages 639-650
Cheng Zhang, Ching-Chang Kuo, Setareh H. Moghadam, Louise Monte, Kenner C. Rice, Robert A. Rissman (Handling Associate Editor: Xuemin Xu)
Corticotropin-Releasing Factor Receptor-1 Antagonism Reduces Oxidative Damage in an Alzheimer’s Disease Transgenic Mouse Model
Abstract: Reports from Alzheimer’s disease (AD) biomarker work have shown a strong link between oxidative stress and AD neuropathology. The nonenzymatic antioxidant, glutathione (GSH), plays a crucial role in defense against reactive oxygen species and maintenance of GSH redox homeostasis. In particular, our previous studies on GSH redox imbalance have implicated oxidative stress induced by excessive reactive oxygen species as a major mediator of AD-like events, with the presence of S-glutathionylated proteins (Pr-SSG) appearing prior to overt AD neuropathology. Furthermore, evidence has demonstrated that oxidative stress may be associated with dysfunction of the hypothalamic-pituitary-adrenal axis, leading to activation of inflammatory pathways and increased production of corticotropin-releasing factor (CRF). Therefore, to investigate whether oxidative insults can be attenuated by reduction of central CRF signaling, we administered the type-1 CRF receptor (CRFR1) selective antagonist, R121919, to AD-transgenic mice beginning in the preclinical/prepathologic period (30-day-old) for 150 days, a timepoint where behavioral impairments and pathologic progression should be measureable. Our results indicate that R121919 treatment can significantly reduce Pr-SSG levels and increase glutathione peroxide activity, suggesting that interference of CRFR1 signaling may be useful as a preventative therapy for combating oxidative stress in AD.
Pages 651-658
Xingbin Wang, Oscar. Lopez, Robert A. Sweet, James T. Becker, Steven T. DeKosky, Mahmud M. Barmada, Eleanor Feingold, F. Yesim Demirci, M. Ilyas. Kamboh
Genetic Determinants of Survival in Patients with Alzheimer’s Disease
Abstract: There is a strong genetic basis for late-onset of Alzheimer’s disease (LOAD), and thus far >20 genes/loci have been identified that affect the risk of LOAD. In addition to disease risk, genetic variation at these loci may also affect components of the natural history of AD, such as survival in AD. In this study, we first examined the role of known LOAD genes with survival time in 983 AD patients. We then performed genome-wide single-nucleotide polymorphism (SNP) and gene-based association analyses to identify novel loci that may influence survival of AD. Survival analysis was conducted using Cox proportional hazards regression under an additive genetics model. We found multiple nominally significant associations (p<0.01) either within or adjacent to known LOAD genes. Genome-wide SNP analysis identified multiple suggestive novel loci and two of them were also significant in gene-based analysis (CCDC85C and NARS2) that survived after controlling for false-discovery rate at 0.05. In summary, we have identified two novel genes for survival in AD that need to be replicated in independent samples. Our findings highlight the importance of focusing on AD-related phenotypes that may help to identify additional genes relevant to AD.
Pages 659-671
Nan Zheng, Peng Yuan, Changhao Li, Jun Wu, Jian Huang (Handling Associate Editor: Annakaisa Haapasalo)
Luteolin Reduces BACE1 Expression through NF-κB and Estrogen Receptor Mediated Pathways in HEK293 and SH-SY5Y Cells
Abstract: Beta-secretase (BACE1) controls an essential step for the generation of amyloid-β peptide (Aβ). As Aβ forms the principle pathologies in Alzheimer’s disease, lowering Aβ production by inhibiting BACE1 is a plausible therapeutic approach. In the present study, we identified a natural polyphenol, luteolin, as a potent inhibitor of BACE1 transcription in human embryonic kidney 293 (HEK293) and human neuroblastoma (SH-SY5Y) cell lines. Luteolin is capable of suppressing the activation of BACE1 promoter by NF-κB signaling. We further characterized that luteolin interferes with NF-κB signaling by both directly and indirectly disrupting p65 complex formation. In addition, we discovered that estrogen receptor mediates luteolin’s effect in inhibiting NF-κB signaling and BACE1 transcription. Interestingly, the beneficial effects of luteolin may be attributed to selective activation profiles of luteolin to different estrogen receptor subtypes. Our study reports luteolin as a potent BACE1-inhibiting compound, providing useful information in understanding estrogen receptor- and NF-κB-mediated signaling in regulating BACE1 expression.
Pages 673-674
Book Review: Bursting Neurons and Fading Memories: An Alternative Hypothesis of the Pathogenesis of Alzheimer’s Disease, by Michael R. D’Andrea, Academic Press, 2014, 170 p., ISBN: 978-0-12-801979-5. Reviewed by Keith A. Crutcher
