International Journal of Alzheimer’s Disease The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Dementia Coding, Workup, and Treatment in the VA New England Healthcare System Wed, 19 Feb 2014 00:00:00 +0000 Growing evidence suggests that Alzheimer’s disease and other types of dementia are underdiagnosed and poorly documented. In our study, we describe patterns of dementia coding and treatment in the Veteran’s Administration New England Healthcare System. We conducted a retrospective cohort study with new outpatient ICD-9 codes for several types of dementia between 2002 and 2009. We examined healthcare utilization, medication use, initial dementia diagnoses, and changes in diagnoses over time by provider type. 8,999 veterans received new dementia diagnoses during the study period. Only 18.3% received a code for cognitive impairment other than dementia, most often “memory loss” (65.2%) prior to dementia diagnosis. Two-thirds of patients received their initial code from a PCP. The etiology of dementia was often never specified by ICD-9 code, even by specialists. Patients followed up exclusively by PCPs had lower rates of neuroimaging and were less likely to receive dementia medication. Emergency room visits and hospitalizations were frequent in all patients but highest in those seen by dementia specialists. Dementia medications are commonly used off-label. Our results suggest that, for the majority the patients, no prodrome of the dementia syndrome is documented with diagnostic code, and patients who do not see dementia specialists have less extensive diagnostic assessment and treatment. Kelly Cho, David R. Gagnon, Jane A. Driver, Arman Altincatal, Nicole Kosik, Stephan Lanes, and Elizabeth V. Lawler Copyright © 2014 Kelly Cho et al. All rights reserved. Novel Point Mutations and A8027G Polymorphism in Mitochondrial-DNA-Encoded Cytochrome c Oxidase II Gene in Mexican Patients with Probable Alzheimer Disease Tue, 18 Feb 2014 07:07:59 +0000 Mitochondrial dysfunction has been thought to contribute to Alzheimer disease (AD) pathogenesis through the accumulation of mitochondrial DNA mutations and net production of reactive oxygen species (ROS). Mitochondrial cytochrome c-oxidase plays a key role in the regulation of aerobic production of energy and is composed of 13 subunits. The 3 largest subunits (I, II, and III) forming the catalytic core are encoded by mitochondrial DNA. The aim of this work was to look for mutations in mitochondrial cytochrome c-oxidase gene II (MTCO II) in blood samples from probable AD Mexican patients. MTCO II gene was sequenced in 33 patients with diagnosis of probable AD. Four patients (12%) harbored the A8027G polymorphism and three of them were early onset (EO) AD cases with familial history of the disease. In addition, other four patients with EOAD had only one of the following point mutations: A8003C, T8082C, C8201T, or G7603A. Neither of the point mutations found in this work has been described previously for AD patients, and the A8027G polymorphism has been described previously; however, it hasn’t been related to AD. We will need further investigation to demonstrate the role of the point mutations of mitochondrial DNA in the pathogenesis of AD. Verónica Loera-Castañeda, Lucila Sandoval-Ramírez, Fermín Paul Pacheco Moisés, Miguel Ángel Macías-Islas, Moisés Alejandro Alatorre Jiménez, Erika Daniela González-Renovato, Fernando Cortés-Enríquez, Alfredo Célis de la Rosa, Irma E. Velázquez-Brizuela, and Genaro Gabriel Ortiz Copyright © 2014 Verónica Loera-Castañeda et al. All rights reserved. Cost Effective Community Based Dementia Screening: A Markov Model Simulation Thu, 06 Feb 2014 11:56:46 +0000 Background. Given the dementia epidemic and the increasing cost of healthcare, there is a need to assess the economic benefit of community based dementia screening programs. Materials and Methods. Markov model simulations were generated using data obtained from a community based dementia screening program over a one-year period. The models simulated yearly costs of caring for patients based on clinical transitions beginning in pre dementia and extending for 10 years. Results. A total of 93 individuals (74 female, 19 male) were screened for dementia and 12 meeting clinical criteria for either mild cognitive impairment or dementia were identified. Assuming early therapeutic intervention beginning during the year of dementia detection, Markov model simulations demonstrated 9.8% reduction in cost of dementia care over a ten-year simulation period, primarily through increased duration in mild stages and reduced time in more costly moderate and severe stages. Discussion. Community based dementia screening can reduce healthcare costs associated with caring for demented individuals through earlier detection and treatment, resulting in proportionately reduced time in more costly advanced stages. Erin Saito, Beau K. Nakamoto, Mario F. Mendez, Bijal Mehta, and Aaron McMurtray Copyright © 2014 Erin Saito et al. All rights reserved. Emotional Working Memory and Alzheimer’s Disease Wed, 05 Feb 2014 00:00:00 +0000 A number of recent studies have reported that working memory does not seem to show typical age-related deficits in healthy older adults when emotional information is involved. Differently, studies about the short-term ability to encode and actively manipulate emotional information in dementia of Alzheimer’s type are few and have yielded mixed results. Here, we review behavioural and neuroimaging evidence that points to a complex interaction between emotion modulation and working memory in Alzheimer’s. In fact, depending on the function involved, patients may or may not show an emotional benefit in their working memory performance. In addition, this benefit is not always clearly biased (e.g., towards negative or positive information). We interpret this complex pattern of results as a consequence of the interaction between multiple factors including the severity of Alzheimer’s disease, the nature of affective stimuli, and type of working memory task. Nicola Mammarella and Beth Fairfield Copyright © 2014 Nicola Mammarella and Beth Fairfield. All rights reserved. Enhancing Diagnostic Accuracy of aMCI in the Elderly: Combination of Olfactory Test, Pupillary Response Test, BDNF Plasma Level, and APOE Genotype Sun, 02 Feb 2014 09:04:02 +0000 Background. Amnestic Mild Cognitive Impairment (aMCI) often progresses to Alzheimer’s disease. There are clinical markers and biomarkers to identify the degenerative process in the brain. Objectives. To obtain the diagnostic values of olfactory test, pupillary response to tropicamide 0.01%, BDNF plasma level, and APOE ε4 in diagnosing aMCI. Methods. Cross-sectional, comparative analysis. Results. There were 109 subjects enrolled (aMCI: 51, normal cognition: 58) with age 64 ± 5.54 years. For diagnosing aMCI, cut-off point for the olfactory score was <7 out of 10 and >22% for pupil dilatation response. Low BDNF plasma level was related significantly with olfactory deficits and aMCI (). Four of five subjects with homozygote e4 presented with multiple-domain aMCI. This group displayed the lowest means of olfactory score and the highest means of pupillary hypersensitivity response (). Combination of olfactory deficit and pupillary hypersensitivity response in detection of aMCI was beneficial with Sp 91% and PPV 87%. In conjunction with clinical markers, BDNF plasma level and presence of APOE e4+ improved Sp and PPV. Conclusions. Combination of olfactory test and pupillary response test was useful as diagnostic tool in aMCI. In conjunction with clinical markers, low level of BDNF plasma and presence of APOE e4 improved the diagnostic value. Yuda Turana, Teguh Asaat S. Ranakusuma, Jan Sudir Purba, Nurmiati Amir, Siti Airiza Ahmad, Moh. Hasan Machfoed, Yvonne Suzy Handayani, Asmarinah, and Sarwono Waspadji Copyright © 2014 Yuda Turana et al. All rights reserved. Neprilysin Is Poorly Expressed in the Prefrontal Cortex of Aged Dogs with Cognitive Dysfunction Syndrome Mon, 06 Jan 2014 16:30:49 +0000 Neprilysin (NEP) is the principal amyloid β (Aβ) degrading peptidase; this activity may protect against Alzheimer’s disease (AD), the most important age-related neurodegenerative process. The aim of this work was to analyze NEP mRNA expression in the frontal cortex of dogs with and without canine cognitive dysfunction syndrome (CDS), which is considered a natural model for AD. Expression of canine cerebral NEP mRNA was assessed by RT-PCR followed by qPCR in young, aged-cognitively unimpaired (CU), and aged-cognitively impaired (CI) dogs. On average, aged-CI dogs showed 80% () lower expression levels of NEP mRNA than their aged-CU counterparts. Furthermore, the standard deviation of the qPCR measurements was more than 6 times higher in the cognitively healthy animals (young and aged-CU) than in the aged-CI group. Another interesting find is the determination of a positive correlation between NEP expression and the number of cholinergic neurons in basal telencephalon, indicating a probable connection between both events in these types of neurodegeneration processes. These results suggest that high expression levels of NEP might be a protective factor for canine CDS and, most likely, for other Aβ-associated neurodegenerative diseases, such as AD. Jesús Canudas, Daniel Insua, Leticia Sarasa, Ángela González-Martínez, María Luisa Suárez, Germán Santamarina, Pedro Pesini, and Manuel Sarasa Copyright © 2014 Jesús Canudas et al. All rights reserved. Spectral Analysis of EEG in Familial Alzheimer’s Disease with E280A Presenilin-1 Mutation Gene Thu, 02 Jan 2014 16:02:55 +0000 To evaluate the hypothesis that quantitative EEG (qEEG) analysis is susceptible to detect early functional changes in familial Alzheimer's disease (AD) preclinical stages. Three groups of subjects were selected from five extended families with hereditary AD: a Probable AD group (18 subjects), an asymptomatic carrier (ACr) group (21 subjects), with the mutation but without any clinical symptoms of dementia, and a normal group of 18 healthy subjects. In order to reveal significant differences in the spectral parameter, the Mahalanobis distance () was calculated between groups. To evaluate the diagnostic efficiency of this statistic , the ROC models were used. The ROC curve was summarized by accuracy index and standard deviation. The using the parameters of the energy in the fast frequency bands shows accurate discrimination between normal and ACr groups (area ROC = 0.89) and between AD probable and ACr groups (area ROC = 0.91). This is more significant in temporal regions. Theses parameters could be affected before the onset of the disease, even when cognitive disturbance is not clinically evident. Spectral EEG parameter could be firstly used to evaluate subjects with E280A Presenilin-1 mutation without impairment in cognitive function. Rene Rodriguez, Francisco Lopera, Alfredo Alvarez, Yuriem Fernandez, Lidice Galan, Yakeel Quiroz, and Maria Antonieta Bobes Copyright © 2014 Rene Rodriguez et al. All rights reserved. KIF6 719Arg Carrier Status Association with Homocysteine and C-Reactive Protein in Amnestic Mild Cognitive Impairment and Alzheimer’s Disease Patients Tue, 24 Dec 2013 18:01:22 +0000 Recent research has demonstrated associations between statin use, KIF6 719Arg carrier status, and cholesterol levels and amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) patients. The association between 719Arg carrier status with homocysteine (tHcy) and c-reactive protein (CRP) levels in aMCI and AD has not been previously investigated. Data from 175 aMCI and AD patients were used for the analysis. 719Arg carriers had significantly lower levels of tHcy than noncarriers (). No significant difference in CRP levels between 719Arg carriers and noncarriers was present (). Logistic regression yielded no significant effect for 719Arg status on CRP [OR = 1.79 (0.85, 3.83), ] but did demonstrate a significant effect for tHcy [OR = 0.44 (0.23, 0.83), ] after adjusting for ApoE carrier status, age, gender, and statin use. This study is the first to explore the relationship between KIF6 719Arg carrier status with tHcy and CRP levels. 719Arg carriers were more likely to have normal tHcy levels after adjusting for ApoE status, age, gender, and statin use. These results suggest that the KIF6 gene might influence cardiovascular pathways associated with AD. Michael Malek-Ahmadi, Amar Patel, and Marwan N. Sabbagh Copyright © 2013 Michael Malek-Ahmadi et al. All rights reserved. Copper Status in Alzheimer’s Disease and Other Neurodegenerative Disorders 2013 Thu, 19 Dec 2013 13:41:06 +0000 Rosanna Squitti, Tjaard Hoogenraad, George Brewer, Ashley I. Bush, and Renato Polimanti Copyright © 2013 Rosanna Squitti et al. All rights reserved. Sensorimotor Cortex Reorganization in Alzheimer's Disease and Metal Dysfunction: A MEG Study Thu, 12 Dec 2013 14:26:07 +0000 Objective. To verify whether systemic biometals dysfunctions affect neurotransmission in living Alzheimer’s disease (AD) patients. Methods. We performed a case-control study using magnetoencephalography to detect sensorimotor fields of AD patients, at rest and during median nerve stimulation. We analyzed position and amount of neurons synchronously activated by the stimulation in both hemispheres to investigate the capability of the primary somatosensory cortex to reorganize its circuitry disrupted by the disease. We also assessed systemic levels of copper, ceruloplasmin, non-Cp copper (i.e., copper not bound to ceruloplasmin), peroxides, transferrin, and total antioxidant capacity. Results. Patients’ sensorimotor generators appeared spatially shifted, despite no change of latency and strength, while spontaneous activity sources appeared unchanged. Neuronal reorganization was greater in moderately ill patients, while delta activity increased in severe patients. Non-Cp copper was the only biological variable appearing to be associated with patient sensorimotor transmission. Conclusions. Our data strengthen the notion that non-Cp copper, not copper in general, affects neuronal activity in AD. Significance. High plasticity in the disease early stages in regions controlling more commonly used body parts strengthens the notion that physical and cognitive activities are protective factors against progression of dementia. C. Salustri, F. Tecchio, F. Zappasodi, L. Tomasevic, M. Ercolani, F. Moffa, E. Cassetta, P. M. Rossini, and R. Squitti Copyright © 2013 C. Salustri et al. All rights reserved. The Beta-Amyloid Protein of Alzheimer’s Disease: Communication Breakdown by Modifying the Neuronal Cytoskeleton Thu, 12 Dec 2013 10:17:02 +0000 Alzheimer’s disease (AD) is one of the most prevalent severe neurological disorders afflicting our aged population. Cognitive decline, a major symptom exhibited by AD patients, is associated with neuritic dystrophy, a degenerative growth state of neurites. The molecular mechanisms governing neuritic dystrophy remain unclear. Mounting evidence indicates that the AD-causative agent, β-amyloid protein (Aβ), induces neuritic dystrophy. Indeed, neuritic dystrophy is commonly found decorating Aβ-rich amyloid plaques (APs) in the AD brain. Furthermore, disruption and degeneration of the neuronal microtubule system in neurons forming dystrophic neurites may occur as a consequence of Aβ-mediated downstream signaling. This review defines potential molecular pathways, which may be modulated subsequent to Aβ-dependent interactions with the neuronal membrane as a consequence of increasing amyloid burden in the brain. Sara H. Mokhtar, Maha M. Bakhuraysah, David S. Cram, and Steven Petratos Copyright © 2013 Sara H. Mokhtar et al. All rights reserved. Neuroinflammation and Copper in Alzheimer’s Disease Thu, 28 Nov 2013 08:45:02 +0000 Inflammation is the innate immune response to infection or tissue damage. Initiation of proinflammatory cascades in the central nervous system (CNS) occurs through recognition of danger associated molecular patterns by cognate immune receptors expressed on inflammatory cells and leads to rapid responses to remove the danger stimulus. The presence of activated microglia and astrocytes in the vicinity of amyloid plaques in the brains of Alzheimer’s disease (AD) patients and mouse models implicates inflammation as a contributor to AD pathogenesis. Activated microglia play a critical role in amyloid clearance, but chronic deregulation of CNS inflammatory pathways results in secretion of neurotoxic mediators that ultimately contribute to neurodegeneration in AD. Copper (Cu) homeostasis is profoundly affected in AD, and accumulated extracellular Cu drives Aβ aggregation, while intracellular Cu deficiency limits bioavailable Cu required for CNS functions. This review presents an overview of inflammatory events that occur in AD in response to Aβ and highlights recent advances on the role of Cu in modulation of beneficial and detrimental inflammatory responses in AD. Xin Yi Choo, Lobna Alukaidey, Anthony R. White, and Alexandra Grubman Copyright © 2013 Xin Yi Choo et al. All rights reserved. Effects of Copper and/or Cholesterol Overload on Mitochondrial Function in a Rat Model of Incipient Neurodegeneration Wed, 06 Nov 2013 14:39:56 +0000 Copper (Cu) and cholesterol (Cho) are both associated with neurodegenerative illnesses in humans and animals models. We studied the effect in Wistar rats of oral supplementation with trace amounts of Cu (3 ppm) and/or Cho (2%) in drinking water for 2 months. Increased amounts of nonceruloplasmin-bound Cu were observed in plasma and brain hippocampus together with a higher concentration of ceruloplasmin in plasma, cortex, and hippocampus. Cu, Cho, and the combined treatment Cu + Cho were able to induce a higher Cho/phospholipid ratio in mitochondrial membranes with a simultaneous decrease in glutathione content. The concentration of cardiolipin decreased and that of peroxidation products, conjugated dienes and lipoperoxides, increased. Treatments including Cho produced rigidization in both the outer and inner mitochondrial membranes with a simultaneous increase in permeability. No significant increase in Cyt C leakage to the cytosol was observed except in the case of cortex from rats treated with Cu and Cho nor were there any significant changes in caspase-3 activity and the Bax/Bcl2 ratio. However, the Aβ(1–42)/(1–40) ratio was higher in cortex and hippocampus. These findings suggest an incipient neurodegenerative process induced by Cu or Cho that might be potentiated by the association of the two supplements. Nathalie Arnal, Omar Castillo, María J. T. de Alaniz, and Carlos A. Marra Copyright © 2013 Nathalie Arnal et al. All rights reserved. Role of Copper and Cholesterol Association in the Neurodegenerative Process Tue, 29 Oct 2013 10:26:41 +0000 Age is one of the main factors involved in the development of neurological illnesses, in particular, Alzheimer, and it is widely held that the rapid aging of the world population is accompanied by a rise in the prevalence and incidence of Alzheimer disease. However, evidence from recent decades indicates that Cu and Cho overload are emerging causative factors in neurodegeneration, a hypothesis that has been partially investigated in experimental models. The link between these two variables and the onset of Alzheimer disease has opened up interesting new possibilities requiring more in-depth analysis. The aim of the present study was therefore to investigate the effect of the association of Cu + Cho (CuCho) as a possible synergistic factor in the development of an Alzheimer-like pathology in Wistar rats. We measured total- and nonceruloplasmin-bound Cu and Cho (free and sterified) contents in plasma and brain zones (cortex and hippocampus), markers of oxidative stress damage, inflammation, and programmed cell death (caspase-3 and calpain isoforms). The ratio beta-amyloid (1-42)/(1-40) was determined in plasma and brain as neurodegenerative biomarker. An evaluation of visuospatial memory (Barnes maze test) was also performed. The results demonstrate the establishment of a prooxidative and proinflammatory environment after CuCho treatment, hallmarked by increased TBARS, protein carbonyls, and nitrite plus nitrate levels in plasma and brain zones (cortex and hippocampus) with a consequent increase in the activity of calpains and no significant changes in caspase-3. A simultaneous increase in the plasma Aβ1-42/Aβ1-40 ratio was found. Furthermore, a slight but noticeable change in visuospatial memory was observed in rats treated with CuCho. We conclude that our model could reflect an initial stage of neurodegeneration in which Cu and Cho interact with one another to exacerbate neurological damage. Nathalie Arnal, Gustavo R. Morel, María J. T. de Alaniz, Omar Castillo, and Carlos A. Marra Copyright © 2013 Nathalie Arnal et al. All rights reserved. Virtual Screening and Biological Evaluation of Piperazine Derivatives as Human Acetylcholinesterase Inhibitors Mon, 28 Oct 2013 14:56:31 +0000 The piperazine derivatives have been shown to inhibit human acetylcholinesterase. Virtual screening by molecular docking of piperazine derivatives 1-(1,4-benzodioxane-2-carbonyl) piperazine (K), 4-(4-methyl)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S1), and 4-(4-chloro)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S3) has been shown to bind at peripheral anionic site and catalytic sites, whereas 4-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S4) and 4-(2,5-dichloro)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S7) do not bind either to peripheral anionic site or catalytic site with hydrogen bond. All the derivatives have differed in number of H-bonds and hydrophobic interactions. The peripheral anionic site interacting molecules have proven to be potential therapeutics in inhibiting amyloid peptides aggregation in Alzheimer’s disease. All the piperazine derivatives follow Lipinski’s rule of five. Among all the derivatives 1-(1,4-benzodioxane-2-carbonyl) piperazine (K) was found to have the lowest TPSA value. Kavitha Raj Varadaraju, Jajur Ramanna Kumar, Lingappa Mallesha, Archana Muruli, Kikkeri Narasimha Shetty Mohana, Chethan Kumar Mukunda, and Umesha Sharanaiah Copyright © 2013 Kavitha Raj Varadaraju et al. All rights reserved. Family Composition and Expressions of Family-Focused Care Needs at an Academic Memory Disorders Clinic Tue, 22 Oct 2013 15:15:26 +0000 Objective. To understand who dementia patients identify as their family and how dementia affects family life. Background. Dementia care is often delivered in family settings, so understanding the constituency and needs of the family unit involved in care is important for determining contributors to family quality of life. Design/Methods. Seventy-seven families receiving care at an academic dementia clinic completed questionnaires regarding the affected person and the family. Responses were categorized as focused on an individual’s needs or the family’s needs. Results. Respondents identified a mean of 3.77 family members involved in care. Spouse (80.5%), daughter (58.4%), son (46.8%), and stepchild or child-in-law (37.7%) were the most frequently listed family members. Questions regarding the effect of dementia-related changes in cognition and mood were most likely to elicit a family-focused response. Questionnaire items that inquired about specific medical questions and strategies to improve family function were least likely to elicit a family-focused response. Conclusions. Both caregivers and persons with dementia frequently provided family-focused responses, supporting the construct of dementia as an illness that affects life in the family unit. This finding reinforces the potential utility of family-centered quality of life measures in assessing treatment success for people with dementia. Brandalyn C. Riedel, Jamie K. Ducharme, and David S. Geldmacher Copyright © 2013 Brandalyn C. Riedel et al. All rights reserved. Decreased Copper in Alzheimer’s Disease Brain Is Predominantly in the Soluble Extractable Fraction Mon, 21 Oct 2013 09:23:55 +0000 Alzheimer’s disease (AD) is the leading cause of dementia and represents a significant burden on the global economy and society. The role of transition metals, in particular copper (Cu), in AD has become of significant interest due to the dyshomeostasis of these essential elements, which can impart profound effects on cell viability and neuronal function. We tested the hypothesis that there is a systemic perturbation in Cu compartmentalization in AD, within the brain as well as in the periphery, specifically within erythrocytes. Our results showed that the previously reported decrease in Cu within the human frontal cortex was confined to the soluble () and total homogenate () fractions. No differences were observed in Cu concentration in erythrocytes. Our data indicate that there is a brain specific alteration in Cu levels in AD localized to the soluble extracted material, which is not reflected in erythrocytes. Further studies using metalloproteomics approaches will be able to elucidate the metabolic mechanism(s) that results in the decreased brain Cu levels during the progression of AD. Alan Rembach, Dominic J. Hare, Monica Lind, Christopher J. Fowler, Robert A. Cherny, Catriona McLean, Ashley I. Bush, Colin L. Masters, and Blaine R. Roberts Copyright © 2013 Alan Rembach et al. All rights reserved. Cardiovascular Risk and Hippocampal Thickness in Alzheimer’s Disease Mon, 21 Oct 2013 08:57:56 +0000 Cardiovascular risk factors influence onset and progression of Alzheimer’s disease. Among cognitively healthy people, changes in brain structure and function associated with high blood pressure, diabetes, or other vascular risks suggest differential regional susceptibility to neuronal damage. In patients with Alzheimer’s disease, hippocampal and medial temporal lobe atrophy indicate early neuronal loss preferentially in key areas for learning and memory. We wanted to investigate whether this regional cortical thinning would be modulated by cardiovascular risk factors. We utilized high-resolution magnetic resonance imaging and a cortical unfolding technique to determine the cortical thickness of medial temporal subregions in 30 patients with Alzheimer’s disease. Cardiovascular risk was assessed using a sex-specific multivariable risk score. Greater cardiovascular risk was associated with cortical thinning in the hippocampus CA2/3/dentate gyrus area but not other hippocampal and medial temporal subregions. APOE genotype, a family history of Alzheimer’s disease, and age did not influence cortical thickness. Alzheimer’s disease-related atrophy could mask the influence of genetic risk factors or age on regional cortical thickness in medial temporal lobe regions, whereas the impact of vascular risk factors remains detectable. This highlights the importance of cardiovascular disease prevention and treatment in patients with Alzheimer’s disease. Markus Donix, Maria Scharf, Kira Marschner, Annett Werner, Cathrin Sauer, Antje Gerner, Josef A. Nees, Shirin Meyer, Katharina L. Donix, Rüdiger Von Kummer, and Vjera A. Holthoff Copyright © 2013 Markus Donix et al. All rights reserved. Zinc Deficiency and Zinc Therapy Efficacy with Reduction of Serum Free Copper in Alzheimer’s Disease Thu, 10 Oct 2013 13:37:19 +0000 We are in the midst of an epidemic of Alzheimer’s disease (AD) in developed countries. We have postulated that ingestion of inorganic copper from drinking water and taking supplement pills and a high fat diet are major causative factors. Ingestion of inorganic copper can directly raise the blood free copper level. Blood free copper has been shown by the Squitti group to be elevated in AD, to correlate with cognition, and to predict cognition loss. Secondly, we have shown that AD patients are zinc deficient compared to age matched controls. Zinc is important in neuronal protection. We carried out a 6-month small double blind trial of a new zinc formulation on AD patients. We found that in patients 70 years and older, zinc therapy protected against cognition decline compared to placebo controls. We also found that zinc therapy significantly lowered blood free copper levels. So zinc efficacy could be due to restoring neuronal zinc levels, to lowering blood free copper levels, or to both. George J. Brewer and Sukhvir Kaur Copyright © 2013 George J. Brewer and Sukhvir Kaur. All rights reserved. Preferential Selectivity of Inhibitors with Human Tau Protein Kinase Gsk3 Elucidates Their Potential Roles for Off-Target Alzheimer’s Therapy Thu, 10 Oct 2013 13:28:32 +0000 Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid beta peptides (A) and neurofibrillary tangles (NFTs). The abnormal phosphorylation of tau leads to the formation of NFTs produced by the action of tau kinases, resulting in the loss of neurons and synapse, leading to dementia. Hence, tau kinases have become potential drug target candidates for small molecule inhibitors. With an aim to explore the identification of a common inhibitor, this investigation was undertaken towards analyzing all 10 tau kinases which are implicated in phosphorylation of AD. A set of 7 inhibitors with varied scaffolds were collected from the Protein Data Bank (PDB). The analysis, involving multiple sequence alignment, 3D structural alignment, catalytic active site overlap, and docking studies, has enabled elucidation of the pharmacophoric patterns for the class of 7 inhibitors. Our results divulge that tau protein kinases share a specific set of conserved structural elements for the binding of inhibitors and ATP, respectively. The scaffold of 3-aminopyrrolidine (inhibitor 6) exhibits high preferential affinity with GSK3. Surprisingly, the PDB does not contain the structural details of GSK3 with this specific inhibitor. Thus, our investigations provide vital clues towards design of novel off-target drugs for Alzheimer’s. Jagadeesh Kumar Dasappa and H. G. Nagendra Copyright © 2013 Jagadeesh Kumar Dasappa and H. G. Nagendra. All rights reserved. Clinical Trial of a Home Safety Toolkit for Alzheimer’s Disease Sun, 29 Sep 2013 09:32:12 +0000 This randomized clinical trial tested a new self-directed educational intervention to improve caregiver competence to create a safer home environment for persons with dementia living in the community. The sample included 108 patient/caregiver dyads: the intervention group () received the Home Safety Toolkit (HST), including a new booklet based on health literacy principles, and sample safety items to enhance self-efficacy to make home safety modifications. The control group () received customary care. Participants completed measures at baseline and at twelve-week follow-up. Multivariate Analysis of Covariance (MANCOVA) was used to test for significant group differences. All caregiver outcome variables improved in the intervention group more than in the control. Home safety was significant at , caregiver strain at , and caregiver self-efficacy at . Similarly, the care receiver outcome of risky behaviors and accidents was lower in the intervention group (). The self-directed use of this Home Safety Toolkit activated the primary family caregiver to make the home safer for the person with dementia of Alzheimer's type (DAT) or related disorder. Improving the competence of informal caregivers is especially important for patients with DAT in light of all stakeholders reliance on their unpaid care. Kathy J. Horvath, Scott A. Trudeau, James L. Rudolph, Paulette A. Trudeau, Mary E. Duffy, and Dan Berlowitz Copyright © 2013 Kathy J. Horvath et al. All rights reserved. Alpha 1-Antichymotrypsin, an Inflammatory Protein Overexpressed in the Brains of Patients with Alzheimer’s Disease, Induces Tau Hyperphosphorylation through c-Jun N-Terminal Kinase Activation Mon, 23 Sep 2013 11:48:52 +0000 The association of inflammatory proteins with neuritic plaques in the brains of Alzheimer’s disease (AD) patients has led to the hypothesis that inflammation plays a pivotal role in the development of pathology in AD. Earlier studies have shown that alpha 1-antichymotrypsin (ACT) enhances amyloid beta fibrillization and accelerated plaque formation in APP transgenic mice. Later studies from our laboratory have shown that purified ACT induces tau hyperphosphorylation and degeneration in neurons. In order to understand the mechanisms by which inflammatory proteins enhance tau hyperphosphorylation, we injected interleukin-1β (IL-1β) intracerebroventricularly into mice expressing human ACT, human tau, or both transgenes. It was found that the hyperphosphorylation of tau in ACT and ACT/htau mice after IL-1β injection correlated with increased phosphorylation of c-Jun N-terminal kinase (JNK). We verified the involvement of JNK in ACT-induced tau phosphorylation by utilizing JNK inhibitors in cultured primary neurons treated with ACT, and we found that the inhibitor showed complete prevention of ACT-induced tau phosphorylation. These results indicate that JNK is one of the major kinases involved in the ACT-mediated tau hyperphosphorylation and suggest that inhibitors of this kinase may protect against inflammation-induced tau hyperphosphorylation and neurodegeneration associated with AD. Ethika Tyagi, Tina Fiorelli, Michelle Norden, and Jaya Padmanabhan Copyright © 2013 Ethika Tyagi et al. All rights reserved. Neuroprotective Role of a Novel Copper Chelator against Induced Neurotoxicity Wed, 18 Sep 2013 09:16:38 +0000 Alzheimer's disease (AD) is a progressive neurodegenerative disease and associated with the extracellular deposits of amyloid-β peptide in hippocampus region. Metal ions like Cu, Fe and Zn are known to associate with the amyloid beta (Aβ) at high concentration and interaction of these ions with soluble and aggregated forms of Aβ peptide help in development of AD. Here we showed Cu mediated neurotoxicity in the eye tissues of transgenic Drosophila expressing human amyloid β and its rescue through a novel Cu chelator. In this context, we have synthesised and characterized the compound L 2,6-Pyridinedicarboxylic acid, 2,6-bis[2-[(4-carboxyphenyl) methylene] hydrazide] by Mass spectra (MS) and Elemental analysis (EA). The Cu chelation potential of the compound L is tested in vivo in Drosophila. Oral administration of Copper to the transgenic larvae resulted in severe degeneration in eye tissues, which was rescued by the supplementation of compound L. The levels of anti-oxidant markers like SOD and MDA were measured in compound L treated flies and found a significant rescue (). Further rescue of the eye degeneration phenotypes as revealed by SEM affirm the role of copper in Aβ toxicity. Hence, use of compound L, an amidoamine derivative, could be a possible therapeutic measure for Aβ induced neurotoxicity. Sandeep Kumar Singh, Priti Sinha, L. Mishra, and S. Srikrishna Copyright © 2013 Sandeep Kumar Singh et al. All rights reserved. Acetylcholinesterase Inhibitors Promote Angiogenesis in Chick Chorioallantoic Membrane and Inhibit Apoptosis of Endothelial Cells Mon, 16 Sep 2013 08:44:44 +0000 Alzheimer’s disease (AD) is one of the most common causes of dementia in the elderly. Recently, a great attention has been paid to the possible role of vascular changes in the pathogenesis of AD. Reduced microvascular density and degeneration of the endothelium are of structural cerebrovascular changes in AD. Acetylcholinesterase (AChE) inhibitors are widely used for the improvement of AD symptoms. Until now, however, the effects of AChE inhibitors on vascular changes including angiogenesis and endothelial cell apoptosis are not fully understood. In the present work, the effects of three AChE inhibitors (donepezil, rivastigmine, and galantamine) were tested on H2O2-induced apoptosis in human umbilical vein endothelial cells (HUVECs) and on angiogenesis in chicken chorioallantoic membrane model. Incubation of HUVEC with H2O2 led to a significant decrease in cell viability and an increase in the percentage of apoptotic cells. The tested drugs, at concentrations of 1–100 μM, significantly inhibited the H2O2-induced toxicity. Also, all donepezil, rivastigmine and galantamine significantly increased the number of vessels in the chorioallantoic membrane when injected into fertilized eggs. In conclusion, AChE inhibitors possess angiogenesis-accelerating properties and have antiapoptotic effects on endothelial cells. These effects of AChE inhibitors may be involved in their beneficial effects on AD. Seyed Mohsen Mortazavian, Heydar Parsaee, Seyed Hadi Mousavi, Zahra Tayarani-Najaran, Ahmad Ghorbani, and Hamid Reza Sadeghnia Copyright © 2013 Seyed Mohsen Mortazavian et al. All rights reserved. Cumulative Effect of Depression on Dementia Risk Thu, 12 Sep 2013 11:06:52 +0000 Objective. To analyze a potential cumulative effect of life-time depression on dementia and Alzheimer’s disease (AD), with control of vascular factors (VFs). Methods. This study was a subanalysis of the Neurological Disorders in Central Spain (NEDICES) study. Past and present depression, VFs, dementia status, and dementia due to AD were documented at study inception. Dementia status was also documented after three years. Four groups were created according to baseline data: never depression (nD), past depression (pD), present depression (prD), and present and past depression (prpD). Logistic regression was used. Results. Data of 1,807 subjects were investigated at baseline (mean age 74.3, 59.3% women), and 1,376 (81.6%) subjects were evaluated after three years. The prevalence of dementia at baseline was 6.7%, and dementia incidence was 6.3%. An effect of depression was observed on dementia prevalence (OR [CI 95%] 1.84 [1.01–3.35] for prD and 2.73 [1.08–6.87] for prpD), and on dementia due to AD (OR 1.98 [0.98–3.99] for prD and OR 3.98 [1.48–10.71] for prpD) (fully adjusted models, nD as reference). Depression did not influence dementia incidence. Conclusions. Present depression and, particularly, present and past depression are associated with dementia at old age. Multiple mechanisms, including toxic effect of depression on hippocampal neurons, plausibly explain these associations. J. Olazarán, R. Trincado, and F. Bermejo-Pareja Copyright © 2013 J. Olazarán et al. All rights reserved. Cholesterol and Copper Affect Learning and Memory in the Rabbit Thu, 29 Aug 2013 14:17:45 +0000 A rabbit model of Alzheimer’s disease based on feeding a cholesterol diet for eight weeks shows sixteen hallmarks of the disease including beta amyloid accumulation and learning and memory changes. Although we have shown that feeding 2% cholesterol and adding copper to the drinking water can retard learning, other studies have shown that feeding dietary cholesterol before learning can improve acquisition and feeding cholesterol after learning can degrade long-term memory. We explore the development of this model, the issues surrounding the role of copper, and the particular contributions of the late D. Larry Sparks. Bernard G. Schreurs Copyright © 2013 Bernard G. Schreurs. All rights reserved. Utility of the Mini-Cog for Detection of Cognitive Impairment in Primary Care: Data from Two Spanish Studies Wed, 28 Aug 2013 08:47:48 +0000 Objectives. To study the utility of the Mini-Cog test for detection of patients with cognitive impairment (CI) in primary care (PC). Methods. We pooled data from two phase III studies conducted in Spain. Patients with complaints or suspicion of CI were consecutively recruited by PC physicians. The cognitive diagnosis was performed by an expert neurologist, after formal neuropsychological evaluation. The Mini-Cog score was calculated post hoc, and its diagnostic utility was evaluated and compared with the utility of the Mini-Mental State (MMS), the Clock Drawing Test (CDT), and the sum of the MMS and the CDT () using the area under the receiver operating characteristic curve (AUC). The best cut points were obtained on the basis of diagnostic accuracy (DA) and kappa index. Results. A total sample of 307 subjects (176 CI) was analyzed. The Mini-Cog displayed an AUC (±SE) of , which was significantly inferior to the AUC of the CDT (), the MMS (), and the (). The best cut point of the Mini-Cog was 1/2 (sensitivity 0.60, specificity 0.90, DA 0.73, and kappa index ). Conclusions. The utility of the Mini-Cog for detection of CI in PC was very modest, clearly inferior to the MMS or the CDT. These results do not permit recommendation of the Mini-Cog in PC. Cristóbal Carnero-Pardo, Isabel Cruz-Orduña, Beatriz Espejo-Martínez, Carolina Martos-Aparicio, Samuel López-Alcalde, and Javier Olazarán Copyright © 2013 Cristóbal Carnero-Pardo et al. All rights reserved. Studies on Interaction of Buffalo Brain Cystatin with Donepezil: An Alzheimer's Drug Sun, 25 Aug 2013 13:22:07 +0000 When drugs bind to a protein, the intramolecular structures can be altered, resulting in conformational change of the protein. Donepezil, an Acetyl Cholinesterase inhibitor (AChE), is commonly prescribed to patients with Alzheimer's disease (AD) to enhance cholinergic neurotransmission. It is the “first-line” agents in the treatment of Alzheimer's disease used to improve cognitive function in the disease. In the present study, a cysteine protease inhibitor (cystatin) has been isolated from buffalo brain using alkaline treatment, 40 to 60% ammonium sulphate fractionation and gel filtration chromatography on Sephadex G-75 with % yield of 64.13 and fold purification of 384.7. The purified inhibitor (Buffalo Brain Cystatin, (BBC)) was eluted as a single papain inhibitory peak which migrated as single band on native PAGE; however, on SDS-PAGE with and without beta mercaptoethanol (βME) BBC gave two bands of M W 31.6 and 12.4 KDa, respectively. The molecular weight determined by gel filtration came out to be 43.6 KDa. The UV spectra of cystatin on interaction with donepezil suggested a conformational change in the protein. The fluorescence spectra of BC-donepezil composite show structural changes indicating 40 nm red shift with significant increase in fluorescence intensity of cystatin in the presence of donepezil representing an unfolding of cystatin on interaction, which is an indication of side effect of donepezil during the use of this drug. Fakhra Amin and Bilqees Bano Copyright © 2013 Fakhra Amin and Bilqees Bano. All rights reserved. γ-Secretase Pharmacology: What Pharmacology Will Work for Alzheimer's Disease? Thu, 18 Apr 2013 19:25:50 +0000 Jeremy H. Toyn, Adele Rowley, Yasuji Matsuoka, Taisuke Tomita, and Bruno P. Imbimbo Copyright © 2013 Jeremy H. Toyn et al. All rights reserved. Care for Alzheimer's Disease Thu, 18 Apr 2013 18:57:50 +0000 Hiroyuki Umegaki, Hajime Takechi, and Hiroko H. Dodge Copyright © 2013 Hiroyuki Umegaki et al. All rights reserved.