International Journal of Alzheimer’s Disease The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Enhancing Resourcefulness to Improve Outcomes in Family Caregivers and Persons with Alzheimer’s Disease: A Pilot Randomized Trial Mon, 29 Sep 2014 00:00:00 +0000 This pilot randomized trial tested an intervention aimed at enhancing resourcefulness in family caregivers of persons with dementia, postulating that caregivers’ emotional outcomes (anxiety and depression) and role outcomes (reward, strain, mutuality, and preparedness) would be improved, and problem behaviors in the care recipients (persons with dementia) would be reduced as a result of the intervention. Subjects were stratified by race (white or African American) and by baseline resourcefulness (high or low). Family caregivers were randomly assigned to an intervention group in which subjects attended six resourcefulness training sessions, meeting for 2 hours weekly over 6 weeks, or to a control group that received no treatment. Small to medium effects were shown for the intervention program on resourcefulness, anxiety, and preparedness of the caregivers and on frequency of behavior problems in the care recipients. Caregivers in the intervention group reported significantly more resourcefulness skills, with a medium effect at week 6 and a small effect 12 weeks later, compared with the control group. Persons with dementia had fewer behavior problems in the intervention group compared with control, although the difference was not significant. Caregivers’ anxiety was reduced in the intervention group at 12 weeks. Elizabeth W. Gonzalez, Marcia Polansky, Carol F. Lippa, Laura N. Gitlin, and Jaclene A. Zauszniewski Copyright © 2014 Elizabeth W. Gonzalez et al. All rights reserved. The Role of the Blood-Brain Barrier in the Pathogenesis of Senile Plaques in Alzheimer’s Disease Thu, 18 Sep 2014 12:49:22 +0000 The accumulation of beta-amyloid [Aβ] within senile plaques [SP] is characteristic of these lesions in Alzheimer’s disease. The accumulation of Aβ42, in particular, in the superior temporal [ST] cortex may result from an inability of the blood brain barrier (BBB) to regulate the trans-endothelial transport and clearance of the amyloid. Lipoprotein receptor-related protein [LRP] and P-glycoprotein [P-gp] facilitate the efflux of Aβ out of the brain, whereas receptor for advanced glycation end products [RAGE] facilitates Aβ influx. Additionally, vascular endothelial growth factor [VEGF] and endothelial nitric oxide synthase [eNOS] may influence the trans-BBB transport of Aβ. In this study we examined ST samples and compared SP burden of all types with the capillary expression of LRP, p-gp, RAGE, VEGF, and e-NOS in samples from 15 control and 15 Alzheimer brains. LRP, P-gp, RAGE, VEGF, and eNOS positive capillaries and Aβ42 plaques were quantified and statistical analysis of the nonparametric data was performed using the Mann-Whitney and Kruskal-Wallis tests. In the Alzheimer condition P-gp, VEGF, and eNOS positive capillaries were negatively correlated with SP burden, but LRP and RAGE were positively correlated with SP burden. These results indicate altered BBB function in the pathogenesis of SPs in Alzheimer brains. J. Provias and B. Jeynes Copyright © 2014 J. Provias and B. Jeynes. All rights reserved. High-Dimensional Medial Lobe Morphometry: An Automated MRI Biomarker for the New AD Diagnostic Criteria Sun, 31 Aug 2014 06:34:21 +0000 Introduction. Medial temporal lobe atrophy assessment via magnetic resonance imaging (MRI) has been proposed in recent criteria as an in vivo diagnostic biomarker of Alzheimer’s disease (AD). However, practical application of these criteria in a clinical setting will require automated MRI analysis techniques. To this end, we wished to validate our automated, high-dimensional morphometry technique to the hypothetical prediction of future clinical status from baseline data in a cohort of subjects in a large, multicentric setting, compared to currently known clinical status for these subjects. Materials and Methods. The study group consisted of 214 controls, 371 mild cognitive impairment (147 having progressed to probable AD and 224 stable), and 181 probable AD from the Alzheimer’s Disease Neuroimaging Initiative, with data acquired on 58 different 1.5 T scanners. We measured the sensitivity and specificity of our technique in a hierarchical fashion, first testing the effect of intensity standardization, then between different volumes of interest, and finally its generalizability for a large, multicentric cohort. Results. We obtained 73.2% prediction accuracy with 79.5% sensitivity for the prediction of MCI progression to clinically probable AD. The positive predictive value was 81.6% for MCI progressing on average within 1.5 (0.3 s.d.) year. Conclusion. With high accuracy, the technique’s ability to identify discriminant medial temporal lobe atrophy has been demonstrated in a large, multicentric environment. It is suitable as an aid for clinical diagnostic of AD. Simon Duchesne, Fernando Valdivia, Abderazzak Mouiha, and Nicolas Robitaille Copyright © 2014 Simon Duchesne et al. All rights reserved. Drug Utilization Pattern in Patients with Different Types of Dementia in Western India Wed, 27 Aug 2014 08:15:03 +0000 Background. Dementia is one of the most frequent disorders among elderly patients, reaching to epidemic proportions with an estimated 4.6 million new cases globally annually. Partially effective treatments are available for dementia. Aims & Objectives. We aim to study drugs used in dementia and find out frequency of types of Dementia. Method. This was an observational study conducted at rurally based tertiary care hospital. Prospective data was collected from outpatient department, while retrospective data was collected from medical records. Descriptive statistics were used to analyze data. Result. Total 125 prescriptions of patients diagnosed with dementia were analyzed. Alzheimer’s dementia was most common (65.6%), followed by vascular dementia (21.6%), and frontotemporal dementia (10.4%), with the rarest being Lewy body dementia in (2.4%) cases. 60.57% of patients were males. Mini Mental Score Examination mean score was 15.93 ± 1.37. Frontal Battery Assessment mean score was 4.75 ± 1.01. Prescribed drugs were Donepezil (68.49%), Rivastigmine (13.63%), Donepezil + Memantine (6.43%) and Galantamine (12.83%), Quetiapine (38.46%), Lorazepam (23.07%), Clozapine (11.53%), Escitalopram (10.25%), Haloperidol (3.84%), Zolpidem, Sertraline, Olanzepine (2.56%), Nitrazepine, Lamotrigine, Fluoxetine, Tianeptine (1.28%), Folic acid, and Vitamin B12, respectively. Conclusion. Alzheimer’s is the most common type of dementia while Donepezil was the most frequent drug. Mansi Patel, Anuradha Joshi, Jalpa Suthar, and Soaham Desai Copyright © 2014 Mansi Patel et al. All rights reserved. Epidemiology of Dementia among the Elderly in Sub-Saharan Africa Wed, 06 Aug 2014 06:37:55 +0000 Objectives. To review epidemiologic studies on the prevalence, incidence, and risk factors of dementia in sub-Saharan Africa (SSA). Methods. A MEDLINE search (from January 1992 to December 31, 2013) of epidemiologic studies, with no language restriction, was conducted using the keywords “dementia” or “Alzheimer’s” and “Africa.” We selected for review population and hospital-based studies that reported the prevalence, incidence, or risk factors of dementia in SSA in people aged 60 years and above. References of selected articles were reviewed to identify additional relevant articles that met our selection criteria. Results. Of a total of 522 articles, 41 were selected and reviewed. The reported prevalence of dementia in SSA varied widely (range: 2.29%–21.60%); Alzheimer’s disease was the most prevalent type of dementia. Only two studies conducted in Nigeria reported incidence data. Major risk factors identified include older age, female gender, cardiovascular disease, and illiteracy. Conclusion. Data on the epidemiology of dementia in SSA is limited. While earlier studies reported a lower prevalence of dementia in older persons, recent studies have put these findings into question suggesting that dementia prevalence rates in SSA in fact parallel data from Western countries. Olaniyi O. Olayinka and Nadine N. Mbuyi Copyright © 2014 Olaniyi O. Olayinka and Nadine N. Mbuyi. All rights reserved. Comparison of the Inhibition of Monoamine Oxidase and Butyrylcholinesterase Activities by Infusions from Green Tea and Some Citrus Peels Tue, 05 Aug 2014 10:54:36 +0000 This study sought to investigate the effect of infusions from green tea (Camellia sinensis) and some citrus peels [shaddock (Citrus maxima), grapefruit (Citrus paradisi), and orange (Citrus sinensis)] on key enzymes relevant to the management of neurodegenerative conditions [monoamine oxidase (MAO) and butyrylcholinesterase (BChE)]. The total phenol contents and antioxidant activities as typified by their 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radicals scavenging abilities, ferric reducing antioxidant properties, and Fe2+ chelating abilities were also investigated. Green tea had the highest total phenol (43.3 mg/g) and total flavonoid (16.4 mg/g) contents, when compared to orange [total phenol (19.6 mg/g), total flavonoid (6.5 mg/g)], shaddock [total phenol (16.3 mg/g), total flavonoid (5.2 mg/g)], and grapefruit [total phenol (17.7 mg/g), total flavonoid (5.9 mg/g)]. Orange (EC50 = 1.78 mg/mL) had the highest MAO inhibitory ability, while green tea had the least MAO inhibitory ability (EC50 = 2.56 mg/mL). Similarly, green tea had the least BChE inhibitory ability (EC50 = 5.43 mg/mL) when compared to the citrus peels’ infusions. However, green tea infusions had the strongest highest ABTS radical scavenging ability, reducing power, and Fe2+ chelating ability. The inhibition of MAO and BChE activities by the green tea and citrus peels infusions could make them good dietary means for the prevention/management of neurodegenerative conditions. Ayokunle O. Ademosun and Ganiyu Oboh Copyright © 2014 Ayokunle O. Ademosun and Ganiyu Oboh. All rights reserved. The Association between Apolipoprotein E Gene Polymorphism and Mild Cognitive Impairment among Different Ethnic Minority Groups in China Tue, 05 Aug 2014 06:09:00 +0000 The association, in different ethnic groups, of apolipoprotein E (apoE) gene polymorphism with mild cognitive impairment (MCI) has been unclear. Few studies have examined the association in Chinese minorities. The current study explores the association between apoE gene polymorphism and MCI in one of the biggest ethnic groups—the Hui—and compares it with the Han. The Minimental State Exam, Activities of Daily Living Scale, and Geriatric Depression Scale were administered to 306 ethnic Hui and 618 ethnic Han people aged 55 years. ApoE genotypes were determined using the high resolution melting curve method. The distribution of the apoE genotype and the frequency of alleles 2, 3, and 4 were similar in the Hui and Han groups. In analyses adjusted for age, gender, and education level, the 4 allele was a risk factor for MCI in both the Hui group (.61, 95% CI: 1.02–6.66) and the Han group (.36, 95% CI: 1.19–4.67), but the apoE 2 allele was protective for MCI only in the Han group (.48, 95% CI: 0.38–0.88). The association of some apoE genotypes with MCI may differ in different ethnic groups in China. Further studies are needed to explore this effect among different populations. ZhiZhong Wang, Wanrui Ma, Ye Rong, and Lan Liu Copyright © 2014 ZhiZhong Wang et al. All rights reserved. Differential Network Analyses of Alzheimer’s Disease Identify Early Events in Alzheimer’s Disease Pathology Wed, 23 Jul 2014 07:26:26 +0000 In late-onset Alzheimer’s disease (AD), multiple brain regions are not affected simultaneously. Comparing the gene expression of the affected regions to identify the differences in the biological processes perturbed can lead to greater insight into AD pathogenesis and early characteristics. We identified differentially expressed (DE) genes from single cell microarray data of four AD affected brain regions: entorhinal cortex (EC), hippocampus (HIP), posterior cingulate cortex (PCC), and middle temporal gyrus (MTG). We organized the DE genes in the four brain regions into region-specific gene coexpression networks. Differential neighborhood analyses in the coexpression networks were performed to identify genes with low topological overlap (TO) of their direct neighbors. The low TO genes were used to characterize the biological differences between two regions. Our analyses show that increased oxidative stress, along with alterations in lipid metabolism in neurons, may be some of the very early events occurring in AD pathology. Cellular defense mechanisms try to intervene but fail, finally resulting in AD pathology as the disease progresses. Furthermore, disease annotation of the low TO genes in two independent protein interaction networks has resulted in association between cancer, diabetes, renal diseases, and cardiovascular diseases. Jing Xia, David M. Rocke, George Perry, and Monika Ray Copyright © 2014 Jing Xia et al. All rights reserved. Identification and Preclinical Pharmacology of the -Secretase Modulator BMS-869780 Tue, 08 Jul 2014 00:00:00 +0000 Alzheimer’s disease is the most prevalent cause of dementia and is associated with accumulation of amyloid-β peptide (Aβ), particularly the 42-amino acid Aβ1-42, in the brain. Aβ1-42 levels can be decreased by γ-secretase modulators (GSM), which are small molecules that modulate γ-secretase, an enzyme essential for Aβ production. BMS-869780 is a potent GSM that decreased Aβ1-42 and Aβ1-40 and increased Aβ1-37 and Aβ1-38, without inhibiting overall levels of Aβ peptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing by γ-secretase and lowered brain Aβ1-42 without evidence of Notch-related side effects in rats. Human pharmacokinetic (PK) parameters were predicted through allometric scaling of PK in rat, dog, and monkey and were combined with the rat pharmacodynamic (PD) parameters to predict the relationship between BMS-869780 dose, exposure and Aβ1-42 levels in human. Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aβ1-42 lowering. Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued. Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain Aβ1-42 without Notch-related side effects. Jeremy H. Toyn, Lorin A. Thompson, Kimberley A. Lentz, Jere E. Meredith Jr., Catherine R. Burton, Sethu Sankaranararyanan, Valerie Guss, Tracey Hall, Lawrence G. Iben, Carol M. Krause, Rudy Krause, Xu-Alan Lin, Maria Pierdomenico, Craig Polson, Alan S. Robertson, R. Rex Denton, James E. Grace, John Morrison, Joseph Raybon, Xiaoliang Zhuo, Kimberly Snow, Ramesh Padmanabha, Michele Agler, Kim Esposito, David Harden, Margaret Prack, Sam Varma, Victoria Wong, Yingjie Zhu, Tatyana Zvyaga, Samuel Gerritz, Lawrence R. Marcin, Mendi A. Higgins, Jianliang Shi, Cong Wei, Joseph L. Cantone, Dieter M. Drexler, John E. Macor, Richard E. Olson, Michael K. Ahlijanian, and Charles F. Albright Copyright © 2014 Jeremy H. Toyn et al. All rights reserved. A Research on Functional Status, Environmental Conditions, and Risk of Falls in Dementia Mon, 19 May 2014 09:11:41 +0000 This study aimed to determine the effects of disability, physical activity, and functional status as well as environmental conditions on the risk of falls among the elderly with dementia after adjusting for sociodemographic factors. Data were derived from a group including 1210 Malaysian elderly who were demented and noninstitutionalized. The study was a national cross-sectional survey that was entitled “Determinants of Health Status among Older Malaysians.” Approximately 17% of subjects experienced falls. The results showed that ethnic non-Malay and functional decline significantly increased the risk of falls in samples (). The findings indicated that increased environmental quality significantly decreased the risk of falls (). Disability, age, marital status, educational level, sex differences, and physical activity were found irrelevant to the likelihood of falls in subjects (). It was concluded that functional decline and ethnic non-Malay increased the risk of falls but the increased environmental quality reduced falls. Sima Ataollahi Eshkoor, Tengku Aizan Hamid, Siti Sa’adiah Hassan Nudin, and Chan Yoke Mun Copyright © 2014 Sima Ataollahi Eshkoor et al. All rights reserved. Altered Proteolysis in Fibroblasts of Alzheimer Patients with Predictive Implications for Subjects at Risk of Disease Sun, 18 May 2014 14:37:59 +0000 There is great interest in developing reliable biomarkers to support antemortem diagnosis of late-onset Alzheimer’s disease (AD). Early prediction and diagnosis of AD might be improved by the detection of a proteolytic dysfunction in extracts from cultured AD fibroblasts, producing altered isoelectrophoretic forms of the enzyme transketolase (TK-alkaline bands). The TK profile and apolipoprotein E (APOE) genotype were examined in fibroblasts from 36 clinically diagnosed probable late-onset sporadic AD patients and 38 of their asymptomatic relatives, 29 elderly healthy individuals, 12 neurological non-AD patients, and 5 early-onset AD patients. TK alterations occurred in (i) several probable AD patients regardless of age-of-onset and severity of disease; (ii) all early-onset AD patients and APOE ε4/4 carriers; and (iii) nearly half of asymptomatic AD relatives. Normal subjects and non-AD patients were all negative. Notably, culture conditions promoting TK alterations were also effective in increasing active BACE1 levels. Overall, the TK assay might represent a low-cost laboratory tool useful for supporting AD differential diagnosis and identifying asymptomatic subjects who are at greater risk of AD and who should enter a follow-up study. Moreover, the cultured fibroblasts were confirmed as a useful in vitro model for further studies on the pathogenetic process of AD. Alessandra Mocali, Nunzia Della Malva, Claudia Abete, Vito Antonio Mitidieri Costanza, Antonio Bavazzano, Vieri Boddi, Luis Sanchez, Sandra Dessì, Alessandra Pani, and Francesco Paoletti Copyright © 2014 Alessandra Mocali et al. All rights reserved. Electroencephalogram and Alzheimer’s Disease: Clinical and Research Approaches Thu, 24 Apr 2014 13:53:53 +0000 Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by cognitive deficits, problems in activities of daily living, and behavioral disturbances. Electroencephalogram (EEG) has been demonstrated as a reliable tool in dementia research and diagnosis. The application of EEG in AD has a wide range of interest. EEG contributes to the differential diagnosis and the prognosis of the disease progression. Additionally such recordings can add important information related to the drug effectiveness. This review is prepared to form a knowledge platform for the project entitled “Cognitive Signal Processing Lab,” which is in progress in Information Technology Institute in Thessaloniki. The team tried to focus on the main research fields of AD via EEG and recent published studies. Anthoula Tsolaki, Dimitrios Kazis, Ioannis Kompatsiaris, Vasiliki Kosmidou, and Magda Tsolaki Copyright © 2014 Anthoula Tsolaki et al. 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.