Journal of Alzheimer's Disease - Volume 50, issue 4

Authors: Mohseni, Hedieh K. | Chettle, David R.

Article Type: Review Article

Abstract: Aluminum, as an abundant metal, has gained widespread use in human life, entering the body predominantly as an additive to various foods and drinking water. Other major sources of exposure to aluminum include medical, cosmetic, and occupational routes. As a common environmental toxin, with well-known roles in several medical conditions such as dialysis encephalopathy, aluminum is considered a potential candidate in the causality of Alzheimer’s disease. Aluminum mostly accumulates in the bone, which makes bone an indicator of the body burden of aluminum and an ideal organ as a proxy for the brain. Most of the techniques developed for measuring …aluminum include bone biopsy, which requires invasive measures, causing inconvenience for the patients. There has been a considerable effort in developing non-invasive approaches, which allow for monitoring aluminum levels for medical and occupational purposes in larger populations. In vivo neutron activation analysis, a method based on nuclear activation of isotopes of elements in the body and their subsequent detection, has proven to be an invaluable tool for this purpose. There are definite challenges in developing in vivo non-invasive techniques capable of detecting low levels of aluminum in healthy individuals and aluminum-exposed populations. The following review examines the method of in vivo neutron activation analysis in the context of aluminum measurement in humans focusing on different neutron sources, interference from other activation products, and the improvements made in minimum detectable limits and patient dose over the past few decades. Show more

Keywords: Aluminum, Alzheimer’s disease, bone, dementia, gamma spectroscopy, in vivo neutron activation analysis

DOI: 10.3233/JAD-150595

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 913-926, 2016

Authors: Wang, Jun | Tan, Lan | Yu, Jin-tai

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common form of dementia in the elderly. Over the past 20 years, both pharmacological and lifestyle interventions have been studied for AD prevention, but the overall results have been disappointing. The majority of disappointing results have raised questions and great challenges for the future of AD prevention trials. Ongoing advances in the knowledge of pathogenesis, in the identification of novel targets, in improved outcome measures, and in identification and validation of biomarkers may lead to effective strategies for AD prevention. In this paper, we review the selection of participants and interventions, trial design, outcome …assessments, and promising biomarkers in prevention trials, and summarize the lessons learned from completed trials and perspectives from ongoing trials in AD prevention. Selection of optimal participants and interventions, coupled with more refined outcomes and more efficient trial design, may have the capacity to deliver a new era of preventive discovery in this challenging area. Show more

Keywords: Alzheimer’s disease, lifestyle, pharmacology, prevention, trial

DOI: 10.3233/JAD-150826

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 927-945, 2016

Authors: Boccardi, Virginia | Ruggiero, Carmelinda | Patriti, Alberto | Marano, Luigi

Article Type: Review Article

Abstract: A growing concern in patients affected by Alzheimer’s disease (AD) is dysphagia, or swallowing impairment, which leads to malnutrition, dehydration, weight loss, functional decline and fear of eating and drinking, as well as a decrease in the quality of life. Thus the diagnostic assessment of dysphagia in patients with AD is imperative to ensure that they receive effective management, avoiding complications, and reducing comorbidity and mortality in such a growing population. Dysphagia management requires a multidisciplinary approach considering that no single strategy is appropriate for all patients. However, evidence for clinical diagnostic assessment, interventions, and medical management of dysphagia in …these patients are still limited: few studies are reporting the evaluation and the management among this group of patients. Here we analyzed the most recent findings in diagnostic assessment and management of swallowing impairment in patients affected by AD. Show more

Keywords: Alzheimer’s disease, dysphagia, elderly, nutrition

DOI: 10.3233/JAD-150931

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 947-955, 2016

Authors: Balietti, Marta | Giuli, Cinzia | Fattoretti, Patrizia | Fabbietti, Paolo | Postacchini, Demetrio | Conti, Fiorenzo

Article Type: Short Communication

Abstract: We evaluated the effect of cognitive stimulation (CS) on platelet total phospholipases A2 activity (tPLA2 A) in patients with mild cognitive impairment (MCI_P). At baseline, tPLA2 A negatively correlated with Mini-Mental State Examination score (MMSE_s): patients with MMSE_s <26 (Subgroup 1) had significantly higher activity than those with MMSE_s ≥26 (Subgroup 2), who had values similar to the healthy elderly. Regarding CS effect, Subgroup 1 had a significant tPLA2 A reduction, whereas Subgroup 2 did not significantly changes after training. Our results showed for the first time that tPLA2 A correlates with the cognitive conditions of MCI_P, and that …CS acts selectively on subjects with a dysregulated tPLA2 A. Show more

Keywords: Blood platelets, cognitive stimulation, mild cognitive impairment, phospholipases A2

DOI: 10.3233/JAD-150714

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 957-962, 2016

Authors: Rodriguez-Perdigon, Manuel | Solas, Maite | Ramirez, Maria Javier

Article Type: Short Communication

Abstract: In the present work, the involvement of JNK in insulin signaling alterations and its role in glutamatergic deficits in Alzheimer’s disease (AD) has been studied. In postmortem cortical tissues, pJNK levels were increased, while insulin signaling and the expression of VGLUT1 were decreased. A significant correlation was found between reduced expression of insulin receptor and VGLUT1. The administration of a JNK inhibitor reversed the decrease in VGLUT1 expression found in a mice model of insulin resistance. It is suggested that activation of JNK in AD inhibits insulin signaling which could lead to a decreased expression of VGLUT1, therefore contributing to …the glutamatergic deficit in AD. Show more

Keywords: Glutamate, insulin, JNK, Mini-Mental State Examination, pAkt, postmortem human tissue

DOI: 10.3233/JAD-150659

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 963-967, 2016

Authors: Gallucci, Maurizio | Spagnolo, Pierpaolo | Aricò, Maria | Grossi, Enzo

Article Type: Research Article

Abstract: Background: The pharmacological treatment of Alzheimer’s disease (AD) is based largely on cholinesterase inhibitors (ChEI). Objective: To investigate whether or not some non-pharmacological and contextual factors measured prior to starting treatment such as past occupation, lifestyles, marital status, degree of autonomy and cognitive impairment, living alone or with others, and the degree of brain atrophy are associated with a better response to ChEI treatment. Methods: Eighty-four AD and six AD with cerebrovascular disease (AD + CVD) outpatients of Treviso Dementia (TREDEM) Registry, with an average cholinesterase inhibitors treatment length of four years, were considered. The outpatients had …undergone a complete evaluation and some non-pharmacological and contextual factors were collected. We defined responder a patient with a delta score T0 – T1 equal or inferior to 2.0 points per year of MMSE and a non-responder a patient with a delta score T0 – T1 superior to 2.0 points per year. In order to identify hidden relationships between variables related to response and non-response, we use a special kind of artificial neural network called Auto-CM, able to create a semantic connectivity map of the variables considered in the study. Results: A higher cognitive profile, a previous intellectual occupation, healthier lifestyles, being married and not living alone, a higher degree of autonomy, and lower degree of brain atrophy at baseline resulted in affecting the response to long-term ChEI therapy. Conclusion: Non-pharmacological and contextual factors appear to influence the effectiveness of treatment with ChEI in the long term. Show more

Keywords: Alzheimer’s disease, Auto-CM system, brain and cognitive reserve, brain atrophy, cholinesterase inhibitors, environmental enrichment, TREDEM

DOI: 10.3233/JAD-150747

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 969-979, 2016

Authors: Belkacemi, Abdenour | Ramassamy, Charles

Article Type: Research Article

Abstract: In Alzheimer’s disease (AD) and in mild cognitive impairment (MCI) patients, by-products of lipid peroxidation such as acrolein accumulated in vulnerable regions of the brain. We have previously shown that acrolein is a highly reactive and neurotoxic aldehyde and its toxicity involves the alteration of several redox-sensitive pathways. Recently, protein-conjugated acrolein in cerebrospinal fluid has been proposed as a biomarker to distinguish between MCI and AD. With growing evidence of the early involvement of oxidative stress in AD etiology, one would expect that a successful therapy should prevent brain oxidative damage. In this regard, several studies have demonstrated that polyphenol-rich …extracts exert beneficial effect on cognitive impairment and oxidative stress. We have recently demonstrated the efficacy of an anthocyanin formulation (MAF14001) against amyloid-β-induced oxidative stress. The aim of this study is to investigate the neuroprotective effect of MAF14001 as a mixture of anthocyanins, a particular class of polyphenols, against acrolein-induced oxidative damage in SK-N-SH neuronal cells. Our results demonstrated that MAF14001, from 5μ M, was able to efficiently protect SK-N-SH cells against acrolein-induced cell death. MAF14001 was able to lower reactive oxygen species and protein carbonyl levels induced by acrolein. Moreover, MAF1401 prevented glutathione depletion and positively modulated, in the presence of acrolein, some oxidative stress-sensitive pathways including the transcription factors NF-κ B and Nrf2, the proteins γ -GCS and GSK3β, and the protein adaptator p66Shc. Along with its proven protective effect against amyloid-β toxicity, these results demonstrate that MAF14001 could target multiple mechanisms and could be a promising agent for AD prevention. Show more

Keywords: Acrolein, Alzheimer’s disease, anthocyanins, antioxidant, glutathione, oxidative stress, polyphenols

DOI: 10.3233/JAD-150770

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 981-998, 2016

Authors: Gramunt, Nina | Sánchez-Benavides, Gonzalo | Buschke, Herman | Lipton, Richard B. | Masramon, Xavier | Gispert, Juan D. | Peña-Casanova, Jordi | Fauria, Karine | Molinuevo, José L.

Article Type: Research Article

Abstract: Background: Episodic memory testing is fundamental for the diagnosis of Alzheimer’s disease (AD). Although the Free and Cued Selective Reminding Test (FCSRT) is widely used for this purpose, it may not be sensitive enough for early detection of subtle decline in preclinical AD. The Memory Binding Test (MBT) intends to overcome this limitation. Objectives: To analyze the test-retest reliability of the MBT and its convergent validity with the FCRST. Methods: 36 cognitively healthy participants of the ALFA Study, aged 45 to 65, were included for the test-retest study and 69 for the convergent analysis. They were …visited twice in a period of 6 ± 2 weeks. Test-retest reliability was determined by the calculation of the intra-class correlation coefficient (ICC). Score differences were studied by computing the mean percentage of score variation between visits and visualized by Bland-Altman plots. Convergent validity was determined by Pearson’s correlations. Results: ICC values in the test-retest reliability analysis of the MBT direct scores ranged from 0.64 to 0.76. Subjects showed consistent practice effects, with mean amounts of score increasing between 10% and 26%. Pearson correlation between MBT and FCSRT direct scores showed r values between 0.40 and 0.53. The FCSRT displayed ceiling effects not observed in the MBT. Conclusions: The MBT shows adequate test-retest reliability and overall moderate convergent validity with the FCSRT. Unlike the FCSRT, the MBT does not have ceiling effects and it may therefore be especially useful in longitudinal studies, facilitating the measurement of subtle memory performance decline and the detection of very early AD. Show more

Keywords: Alzheimer’s disease, early diagnosis, episodic memory, memory assessment, preclinical, psychometrics, reliability, validity

DOI: 10.3233/JAD-150776

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 999-1010, 2016

Authors: Dodich, Alessandra | Cerami, Chiara | Crespi, Chiara | Canessa, Nicola | Lettieri, Giada | Iannaccone, Sandro | Marcone, Alessandra | Cappa, Stefano F. | Cacioppo, John T.

Article Type: Research Article

Abstract: Cognitive and affective theory of mind (ToM) can be impaired in the course of neurodegenerative dementias. Experimental tests based on different task conditions and/or complexity may fail to capture disease-specific patterns of impairments. In this study, we assessed with a single task both the affective and the cognitive facets of ToM ability in a sample of 47 patients (i.e., 12 AD, 20 bvFTD, and 15 aMCI fulfilling IWG criteria for AD in predementia phase) and 65 healthy controls. Subjects were administered the Story-based Empathy task (SET), a non-verbal task measuring the ability to infer others’ intentions (IA) and emotions (EA) …compared to a control condition (causal inferences, CI). Global and single sub-condition scores were evaluated with a vectorial method, analyzing the relationship between social abilities and basic cognitive functioning by means of two indices representing the basic ability to perform the task and the balance between basic functions and ToM skills. Dementia (AD and bvFTD) patients showed impaired performances on all SET sub-conditions, whereas aMCI subjects’ performance was not different from healthy controls. Vectorial analysis revealed a specific change in the balance between EA and CI conditions only in the bvFTD group, supporting a disproportionate deficit in mental states attribution based on affective cues. The overall deficit in the task in AD appears to be more general and related to the severity of dementia. This latter finding is further supported by the normal performance of the prodromal AD group. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, mild cognitive impairment, neurodegenerative diseases, theory of mind

DOI: 10.3233/JAD-150605

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1011-1022, 2016

Authors: Langlois, Roxane | Joubert, Sven | Benoit, Sophie | Dostie, Valérie | Rouleau, Isabelle

Article Type: Research Article

Abstract: Ribot’s law refers to the better preservation of remote memories compared with recent ones that presumably characterizes retrograde amnesia. Even if Ribot-type temporal gradient has been extensively studied in retrograde amnesia, particularly in Alzheimer’s disease (AD), this pattern has not been consistently found. One explanation for these results may be that rehearsal frequency rather than remoteness accounts for the better preservation of these memories. Thus, the aim of present study was to address this question by studying retrograde semantic memory in subjects with amnestic mild cognitive impairment (aMCI) (n  = 20), mild AD (n  = 20) and in healthy older controls (HC; …n  = 19). In order to evaluate the impact of repetition as well as the impact of remoteness, we used a test assessing memory for enduring and transient public events that occurred in the recent and remote past. Results show no clear temporal gradient across time periods (1960–1975; 1976–1990; 1991–2005; 2006–2011), but a better performance was observed in all three groups for enduring compared with transient events. Moreover, although deficits were globally found in both patients groups compared with HC, more specific analyses revealed that aMCI patients were only impaired on transient events while AD patients were impaired on both transient and enduring events. Exploratory analyses also revealed a tendency suggesting preservation of remote transient events in aMCI. These findings are discussed with regards to memory consolidation models. Show more

Keywords: Alzheimer’s disease, enduring, famous public events, mild cognitive impairment, retrograde memory, semantic memory, transient

DOI: 10.3233/JAD-150722

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1023-1033, 2016

Authors: Eustache, Pierre | Nemmi, Federico | Saint-Aubert, Laure | Pariente, Jeremie | Péran, Patrice

Article Type: Research Article

Abstract: One objective of modern neuroimaging is to identify markers that can aid in diagnosis, monitor disease progression, and impact long-term drug analysis. In this study, physiopathological modifications in seven subcortical structures of patients with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) were characterized by simultaneously measuring quantitative magnetic resonance parameters that are sensitive to complementary tissue characteristics (e.g., volume atrophy, shape changes, microstructural damage, and iron deposition). Fourteen MCI patients and fourteen matched, healthy subjects underwent 3T-magnetic resonance imaging with whole-brain, T1-weighted, T2* -weighted, and diffusion-tensor imaging scans. Volume, shape, mean R2* , mean diffusivity (MD), and mean …fractional anisotropy (FA) in the thalamus, hippocampus, putamen, amygdala, caudate nucleus, pallidum, and accumbens were compared between MCI patients and healthy subjects. Comparisons were then performed using voxel-based analyses of R2* , MD, FA maps, and voxel-based morphometry to determine which subregions showed the greatest difference for each parameter. With respect to the micro- and macro-structural patterns of damage, our results suggest that different and distinct physiopathological processes are present in the prodromal phase of AD. MCI patients had significant atrophy and microstructural changes within their hippocampi and amygdalae, which are known to be affected in the prodromal stage of AD. This suggests that the amygdala is affected in the same, direct physiopathological process as the hippocampus. Conversely, atrophy alone was observed within the thalamus and putamen, which are not directly involved in AD pathogenesis. This latter result may reflect another mechanism, whereby atrophy is linked to indirect physiopathological processes. Show more

Keywords: Alzheimer’s disease, brain, diffusion tensor imaging, iron, magnetic resonance imaging, mild cognitive impairment, multimodal, shape, subcortical structures, volumetry

DOI: 10.3233/JAD-150353

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1035-1050, 2016

Authors: Lacalle-Aurioles, María | Navas-Sánchez, Francisco Javier | Alemán-Gómez, Yasser | Olazarán, Javier | Guzmán-De-Villoria, Juan Adán | Cruz-Orduña, Isabel | Mateos-Pérez, José María | Desco, Manuel

Article Type: Research Article

Abstract: According to the so-called disconnection hypothesis, the loss of synaptic inputs from the medial temporal lobes (MTL) in Alzheimer’s disease (AD) may lead to reduced activity of target neurons in cortical areas and, consequently, to decreased cerebral blood flow (CBF) in those areas. The aim of this study was to assess whether hypoperfusion in parietotemporal and frontal cortices of patients with mild cognitive impairment who converted to AD (MCI-c) and patients with mild AD is associated with atrophy in the MTL and/or microstructural changes in the white matter (WM) tracts connecting these areas. We assessed these relationships by investigating correlations …between CBF in hypoperfused areas, mean cortical thickness in atrophied regions of the MTL, and fractional anisotropy (FA) in WM tracts. In the MCI-c group, a strong correlation was observed between CBF of the superior parietal gyri and FA in the parahippocampal tracts (left: r  = 0.90, p  <  0.0001; right: r  = 0.597, p  = 0.024), and between FA in the right parahippocampal tract and the right precuneus (r  = 0.551, p  = 0.041). No significant correlations between CBF in hypoperfused regions and FA in the WM tract were observed in the AD group. These results suggest an association between perfusion deficits and altered WM tracts in prodromal AD, while microvasculature impairments may have a greater influence in more advanced stages. We did not find correlations between cortical thinning in the medial temporal lobes and decreased FA in the WM tracts of the limbic system in either group. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, disconnection hypothesis, magnetic resonance imaging, mild cognitive impairment, perfusion weighted imaging

DOI: 10.3233/JAD-150288

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1051-1064, 2016

Authors: Wruck, Wasco | Schröter, Friederike | Adjaye, James

Article Type: Research Article

Abstract: Although the incidence of Alzheimer’s disease (AD) is continuously increasing in the aging population worldwide, effective therapies are not available. The interplay between causative genetic and environmental factors is partially understood. Meta-analyses have been performed on aspects such as polymorphisms, cytokines, and cognitive training. Here, we propose a meta-analysis approach based on hierarchical clustering analysis of a reliable training set of hippocampus biopsies, which is condensed to a gene expression signature. This gene expression signature was applied to various test sets of brain biopsies and iPSC-derived neuronal cell models to demonstrate its ability to distinguish AD samples from control. Thus, …our identified AD-gene signature may form the basis for determination of biomarkers that are urgently needed to overcome current diagnostic shortfalls. Intriguingly, the well-described AD-related genes APP and APOE are not within the signature because their gene expression profiles show a lower correlation to the disease phenotype than genes from the signature. This is in line with the differing characteristics of the disease as early-/late-onset or with/without genetic predisposition. To investigate the gene signature’s systemic role(s), signaling pathways, gene ontologies, and transcription factors were analyzed which revealed over-representation of response to stress, regulation of cellular metabolic processes, and reactive oxygen species. Additionally, our results clearly point to an important role of FOXA1 and FOXA2 gene regulatory networks in the etiology of AD. This finding is in corroboration with the recently reported major role of the dopaminergic system in the development of AD and its regulation by FOXA1 and FOXA2. Show more

Keywords: Alzheimer’s disease, energy metabolism, forkhead box proteins, gene expression, induced pluripotent stem cells, meta-analysis, microarray analysis, transcription factors

DOI: 10.3233/JAD-150733

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1065-1082, 2016

Authors: Li, Hsin-Hua | Lin, Shi-Lung | Huang, Chien-Ning | Lu, Fung-Jou | Chiu, Pai-Yi | Huang, Wen-Nung | Lai, Te-Jen | Lin, Chih-Li

Article Type: Research Article

Abstract: Deficiency of insulin signaling has been linked to diabetes and ageing-related neurodegenerative diseases such as Alzheimer’s disease (AD). In this regard, brains exhibit defective insulin receptor substrate-1 (IRS-1) and hence result in alteration of insulin signaling in progression of AD, the most common cause of dementia. Consequently, dysregulation of insulin signaling plays an important role in amyloid-β (Aβ)-induced neurotoxicity. As the derivation of induced pluripotent stem cells (iPSC) involves cell reprogramming, it may provide a means for regaining the control of ageing-associated dysfunction and neurodegeneration via affecting insulin-related signaling. To this, we found that an embryonic stem cell (ESC)-specific microRNA, …miR-302, silences phosphatase and tensin homolog (PTEN) to activate Akt signaling, which subsequently stimulates nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) elevation and hence inhibits Aβ-induced neurotoxicity. miR-302 is predominantly expressed in iPSCs and is known to regulate several important biological processes of anti-oxidative stress, anti-apoptosis, and anti-aging through activating Akt signaling. In addition, we also found that miR-302-mediated Akt signaling further stimulates Nanog expression to suppress Aβ-induced p-Ser307 IRS-1 expression and thus enhances tyrosine phosphorylation and p-Ser 473-Akt/p-Ser 9-GSK3β formation. Furthermore, our in vivo studies revealed that the mRNA expression levels of both Nanog and miR-302-encoding LARP7 genes were significantly reduced in AD patients’ blood cells, providing a novel diagnosis marker for AD. Taken together, our findings demonstrated that miR-302 is able to inhibit Aβ-induced cytotoxicity via activating Akt signaling to upregulate Nrf2 and Nanog expressions, leading to a marked restoration of insulin signaling in AD neurons. Show more

Keywords: Alzheimer’s disease, amyloid-β, insulin signaling, miR-302, Nanog, phosphatase and tensin homolog

DOI: 10.3233/JAD-150741

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1083-1098, 2016

Authors: Kuźma, Elżbieta | Soni, Maya | Littlejohns, Thomas J. | Ranson, Janice M. | van Schoor, Natasja M. | Deeg, Dorly J.H. | Comijs, Hannie | Chaves, Paulo H.M. | Kestenbaum, Bryan R. | Kuller, Lewis H. | Lopez, Oscar L. | Becker, James T. | Langa, Kenneth M. | Henley, William E. | Lang, Iain A. | Ukoumunne, Obioha C. | Llewellyn, David J.

Article Type: Research Article

Abstract: Background: Vitamin D deficiency has been linked with dementia risk, cognitive decline, and executive dysfunction. However, the association with memory remains largely unknown. Objective: To investigate whether low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with memory decline. Methods: We used data on 1,291 participants from the US Cardiovascular Health Study (CHS) and 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, had valid vitamin D measurements, and follow-up memory assessments. The Benton Visual Retention Test (in the CHS) and Rey’s Auditory Verbal Learning Test (in the LASA) were used …to assess visual and verbal memory, respectively. Results: In the CHS, those moderately and severely deficient in serum 25(OH)D changed -0.03 SD (95% CI: –0.06 to 0.01) and –0.10 SD (95% CI: –0.19 to –0.02) per year respectively in visual memory compared to those sufficient (p  = 0.02). In the LASA, moderate and severe deficiency in serum 25(OH)D was associated with a mean change of 0.01 SD (95% CI: –0.01 to 0.02) and –0.01 SD (95% CI: –0.04 to 0.02) per year respectively in verbal memory compared to sufficiency (p  = 0.34). Conclusions: Our findings suggest an association between severe vitamin D deficiency and visual memory decline but no association with verbal memory decline. They warrant further investigation in prospective studies assessing different memory subtypes. Show more

Keywords: Cognition, memory, prospective studies, vitamin D

DOI: 10.3233/JAD-150811

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1099-1108, 2016

Authors: Eketjäll, Susanna | Janson, Juliette | Kaspersson, Karin | Bogstedt, Anna | Jeppsson, Fredrik | Fälting, Johanna | Haeberlein, Samantha Budd | Kugler, Alan R. | Alexander, Robert C. | Cebers, Gvido

Article Type: Research Article

Abstract: A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-β peptide (Aβ) concentrations, plays a key role in the pathogenesis of Alzheimer’s disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-β protein precursor (AβPP) to Aβ peptides, with the soluble N terminal fragment of AβPP (sAβPPβ) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of Aβ. Here, we report the in vitro and in vivo pharmacological …profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40 , Aβ42 , and sAβPPβ. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of Aβ. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293. Show more

Keywords: Alzheimer’s disease, amyloid-β, drug therapy, pharmacology, preclinical drug evaluation

DOI: 10.3233/JAD-150834

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1109-1123, 2016

Authors: Jung, Na-Yeon | Han, Cheol E. | Kim, Hee Jin | Yoo, Sang Wook | Kim, Hee-Jong | Kim, Eun-Joo | Na, Duk L. | Lockhart, Samuel N. | Jagust, William J. | Seong, Joon-Kyung | Seo, Sang Won

Article Type: Research Article

Abstract: The white matter tract-specific correlates of neuropsychological deficits are not fully established in patients with subcortical vascular cognitive impairment (SVCI), where white matter tract damage may be a critical factor in cognitive impairment. The purpose of this study is to investigate the tract-specific correlates of neuropsychological deficits in SVCI patients using tract-specific statistical analysis (TSSA). We prospectively recruited 114 SVCI patients, and 55 age-, gender-, and education-matched individuals with normal cognition (NC). All participants underwent diffusion weighted imaging and neuropsychological testing. We classified tractography results into fourteen major fiber tracts and analyzed group comparison and correlation with cognitive impairments. Relative …to NC subjects, SVCI patients showed decreased fractional anisotropy values in bilateral anterior-thalamic radiation, cingulum, superior-longitudinal fasciculus, uncinate fasciculus, corticospinal tract, and left inferior-longitudinal fasciculus. Focal disruptions in specific tracts were associated with specific cognitive impairments. Our findings suggest that disconnection of specific white matter tracts, especially those neighboring and providing connections between gray matter regions important to certain cognitive functions, may contribute to specific cognitive impairments in SVCI. Show more

Keywords: Diffusion-tensor imaging, neuropsychological correlation, subcortical vascular cognitive impairment, tract-specific statistical analysis, white matter connectivity

DOI: 10.3233/JAD-150841

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1125-1135, 2016

Authors: Luo, Xiao | Qiu, Tiantian | Xu, Xiaojun | Huang, Peiyu | Gu, Quanquan | Shen, Zhujing | Yu, Xinfeng | Jia, YunLu | Guan, Xiaojun | Song, Ruirui | Zhang, Minming | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The apolipoprotein E (APOE) ɛ 4 allele is the best-known genetic risk factor for developing sporadic Alzheimer’s disease (AD). According to neuroimaging studies, the APOE ɛ 4 allele is associated with localized altered brain function. However, in long-range circuitry, APOE ɛ 4 allele-related alterations in functional communication between hemispheres have rarely been directly investigated. We examined the alteration of resting-state functional connectivity (RSFC) between inter-hemispheric homotopic regions in cognitively intact, elderly APOE ɛ 4 carriers. The voxel-mirrored homotopic connectivity method was used to assess the inter-hemispheric RSFC. The current study included 13 cognitively intact, elderly APOE ɛ 4 carriers (with …at least one copy of APOE ɛ 4 allele) and 22 well-matched ɛ 3 homozygotes. Comparisons between the two groups were conducted, and subsequently, the correlation between the differential inter-hemispheric RSFC and cognitive ability was analyzed. Compared with ɛ 3 homozygotes, APOE ɛ 4 carriers showed decreased inter-hemispheric RSFC in the bilateral medial temporal lobe (MTL) and orbital frontal cortex (OFC). Moreover, in APOE ɛ 4 carriers, the inter-hemispheric RSFC of the MTL correlated with the Wechsler Memory Scale-Logical Memory (WMS-LM) (immediate and delayed performance, r  = 0.64, p  <  0.05; r  = 0.65, p  <  0.05, respectively), and the inter-hemispheric RSFC of the OFC correlated with the WMS-LM delayed performance (r  = 0.71, p  <  0.05). In our study, the presence of the APOE ɛ 4 allele was linked with decreased inter-hemispheric RSFC, which was attributed to memory performance in carriers. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, corpus callosum, functional magnetic resonance imaging, memory

DOI: 10.3233/JAD-150989

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1137-1148, 2016

Authors: Zhu, Mingming | Huang, Cong | Ma, Xiao | Wu, Rui | Zhu, Weiwei | Li, Xiaoting | Liang, Zhaofeng | Deng, Feifei | Zhu, Jianyun | Xie, Wei | Yang, Xue | Jiang, Ye | Wang, Shijia | Wu, Jieshu | Geng, Shanshan | Xie, Chunfeng | Zhong, Caiyun

Article Type: Research Article

Abstract: Neuronal cell death is an important feature of neurodegeneration. Aluminum is associated with neurodegenerative disorders, particularly Alzheimer’s disease. However, the underlying mechanisms by which aluminum induces neuronal apoptosis remain to be elucidated. miR-19 is a key miRNA implicated in regulating cell survival process, while the role of miR-19 in Alzheimer’s disease has not been investigated. In the present study, we showed that Aluminum maltolate (Al-malt), a lipophilic Al complex which is a common component of human diet with the ability to facilitate the entry of Al into the brain, induced apoptosis in human neuroblastoma SH-SY5Y cells, along with downregulation of …miR-19a/miR-19b, upregulation of miR-19-targeted PTEN, and alterations of its downstream apoptosis related proteins including AKT, p53, Bax, and Bcl-2. miR-19 overexpression attenuated Al-malt-induced apoptosis as well as changes in the expression of apoptosis related proteins in SH-SY5Y cells. We further revealed that exposure of rats to Al-malt for 12 weeks at doses relevant to human exposure significantly elevated Al concentrations in serum and brain tissues. Al-malt dose-dependently induced apoptosis in rat brain, as evidenced by increased caspase activation and increased TUNEL staining. Consistent with in vitro results, Al-malt reduced miR-19 expression and altered the expression of apoptotic related proteins in rat brain. Taken together, our data suggest for the first time that miR-19 modulation is critically involved in Al-induced neural cell apoptosis. Findings from this study could provide new insight into the molecular mechanisms of Al-associated neurodegenerative pathogenesis. Show more

Keywords: Aluminum, apoptosis, miR-19, modulation, neurodegenerative diseases

DOI: 10.3233/JAD-150763

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1149-1162, 2016

Authors: Zhang, Yudong | Wang, Shuihua | Phillips, Preetha | Yang, Jiquan | Yuan, Ti-Fei

Article Type: Research Article

Abstract: Background: Considering that Alzheimer’s disease (AD) is untreatable, early diagnosis of AD from the healthy elderly controls (HC) is pivotal. However, computer-aided diagnosis (CAD) systems were not widely used due to its poor performance. Objective: Inspired from the eigenface approach for face recognition problems, we proposed an eigenbrain to detect AD brains. Eigenface is only for 2D image processing and is not suitable for volumetric image processing since faces are usually obtained as 2D images. Methods: We extended the eigenbrain to 3D. This 3D eigenbrain (3D-EB) inherits the fundamental strategies in either eigenface or 2D eigenbrain …(2D-EB). All the 3D brains were transferred to a feature space, which encoded the variation among known 3D brain images. The feature space was named as the 3D-EB, and defined as eigenvectors on the set of 3D brains. We compared four different classifiers: feed-forward neural network, support vector machine (SVM) with linear kernel, polynomial (Pol) kernel, and radial basis function kernel. Results: The 50x10-fold stratified cross validation experiments showed that the proposed 3D-EB is better than the 2D-EB. SVM with Pol kernel performed the best among all classifiers. Our “3D-EB + Pol-SVM” achieved an accuracy of 92.81% ± 1.99% , a sensitivity of 92.07% ± 2.48% , a specificity of 93.02% ± 2.22% , and a precision of 79.03% ± 2.37% . Based on the most important 3D-EB U 1 , we detected 34 brain regions related with AD. The results corresponded to recent literature. Conclusions: We validated the effectiveness of the proposed 3D-EB by detecting subjects and brain regions related to AD. Show more

Keywords: Alzheimer’s disease, classification, detection, eigenbrain, machine learning, magnetic resonance imaging, polynomial kernel, prediction, support vector machine

DOI: 10.3233/JAD-150988

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1163-1179, 2016

Authors: Siotto, Mariacristina | Simonelli, Ilaria | Pasqualetti, Patrizio | Mariani, Stefania | Caprara, Deborah | Bucossi, Serena | Ventriglia, Mariacarla | Molinario, Rossana | Antenucci, Mirca | Rongioletti, Mauro | Rossini, Paolo Maria | Squitti, Rosanna

Article Type: Research Article

Abstract: Meta-analyses demonstrate copper involvement in Alzheimer’s disease (AD), and the systemic ceruloplasmin status in relation to copper is an emerging issue. To deepen this matter, we evaluated levels of ceruloplasmin concentration, ceruloplasmin activity, ceruloplasmin specific activity (eCp/iCp), copper, non-ceruloplasmin copper iron, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype in a sample of 84 AD patients and 58 healthy volunteers. From the univariate logistic analyses we found that ceruloplasmin concentration, eCp/iCp, copper, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype were significantly associated with the probability of AD. In the multivariable logistic regression analysis, we selected the best …subset of biological predictors by the forward stepwise procedure. The analysis showed a decrease of the risk of having AD for eCp/iCp (p  = 0.001) and an increase of this risk for non-ceruloplasmin copper (p  = 0.008), age (p  = 0.001), and APOE -ɛ 4 allele (p  <  0.001). The estimated model showed a good power in discriminating AD patients from healthy controls (area under curve: 88% ; sensitivity: 66% ; specificity 93%). These data strength the breakdown of copper homeostasis and propose eCp/iCp as a reliable marker of ceruloplasmin status . Show more

Keywords: Alzheimer’s disease, ceruloplasmin, ceruloplasmin specific activity, non-ceruloplasmin copper

DOI: 10.3233/JAD-150611

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1181-1189, 2016

Authors: Ashby, Emma L. | Miners, James S. | Kehoe , Patrick G. | Love, Seth

Article Type: Research Article

Abstract: Epidemiological data associate hypertension with a predisposition to Alzheimer’s disease (AD), and a number of postmortem and in vivo studies also demonstrate that hypertension increases amyloid-β (Aβ) pathology. In contrast, anti-hypertensive medications reportedly improve cognition and decrease the risk of AD, while certain classes of anti-hypertensive drugs are associated with decreased AD-related pathology. We investigated the effects of hypertension and anti-hypertensive treatment on Aβ plaque load in postmortem frontal cortex in AD. Aβ load was significantly increased in hypertensive (n  = 20) relative to normotensive cases (n  = 62) and was also significantly higher in treated (n  = 9) than untreated hypertensives …(n  = 11). We then looked into mechanisms by which hypertension and treatment might increase Aβ load, focusing on Aβ-synthesizing enzymes, β- and γ -secretase, and Aβ-degrading enzymes, angiotensin-converting enzyme (ACE), insulin-degrading enzyme (IDE) and neprilysin. ACE and IDE protein levels were significantly lower in hypertensive (n  = 21) than normotensive cases (n  = 64), perhaps translating to decreased Aβ catabolism in hypertensives. ACE level was significantly higher in treated (n  = 9) than untreated hypertensives (n  = 12), possibly reflecting feedback upregulation of the renin-angiotensin system. Prospective studies in larger cohorts stratified according to anti-hypertensive drug class are needed to confirm these initial findings and to elucidate the interactions between hypertension, anti-hypertensive treatments, and Aβ metabolism. Show more

Keywords: Angiotensin-converting enzyme, Alzheimer’s disease, amyloid β protein, anti-hypertensive, β-secretase, BACE, γ-secretase, hypertension, insulin-degrading enzyme

DOI: 10.3233/JAD-150831

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1191-1203, 2016

Authors: Kennedy, Richard E. | Cutter, Gary R. | Wang, Guoqiao | Schneider, Lon S.

Article Type: Research Article

Abstract: Background: Many post hoc analyses of clinical trials in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) are in small Phase 2 trials. Subject heterogeneity may lead to statistically significant post hoc results that cannot be replicated in larger follow-up studies. Objective: We investigated the extent of this problem using simulation studies mimicking current trial methods with post hoc analyses based on ApoE4 carrier status. Methods: We used a meta-database of 24 studies, including 3,574 subjects with mild AD and 1,171 subjects with MCI/prodromal AD, to simulate clinical trial scenarios. Post hoc …analyses examined if rates of progression on the Alzheimer’s Disease Assessment Scale-cognitive (ADAS-cog) differed between ApoE4 carriers and non-carriers. Results: Across studies, ApoE4 carriers were younger and had lower baseline scores, greater rates of progression, and greater variability on the ADAS-cog. Up to 18% of post hoc analyses for 18-month trials in AD showed greater rates of progression for ApoE4 non-carriers that were statistically significant but unlikely to be confirmed in follow-up studies. The frequency of erroneous conclusions dropped below 3% with trials of 100 subjects per arm. In MCI, rates of statistically significant differences with greater progression in ApoE4 non-carriers remained below 3% unless sample sizes were below 25 subjects per arm. Conclusions: Statistically significant differences for ApoE4 in post hoc analyses often reflect heterogeneity among small samples rather than true differential effect among ApoE4 subtypes. Such analyses must be viewed cautiously. ApoE genotype should be incorporated into the design stage to minimize erroneous conclusions. Show more

Keywords: Alzheimer’s disease, clinical trials, mild cognitive impairment, statistical analysis, trial design

DOI: 10.3233/JAD-150847

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1205-1215, 2016

Authors: Malara, Alba | De Biase, Giuseppe Andrea | Bettarini, Francesco | Ceravolo, Francesco | Di Cello, Serena | Garo, Michele | Praino, Francesco | Settembrini, Vincenzo | Sgrò, Giovanni | Spadea, Fausto | Rispoli, Vincenzo

Article Type: Research Article

Abstract: Background: Pain is under-detected and undertreated in people with dementia. The present study investigates the prevalence of pain in people with dementia hospitalized in nursing homes that are members of National Association of Third Age Residences (ANASTE) Calabria, and evaluates the association among pain, mood, and behavioral and psychological symptoms of dementia (BPSD). Objective: The aim of this study is to define the prevalence of pain in people with dementia in long term care facilities using scales of self-reporting and observational tools and, particularly, to study the relationship between pain and BPSD. Methods: A prospective observational …study was carried out on 233 patients. Pain assessment was performed using self-reporting tools such as the Numeric Rating Scale (NRS) for patients with slight cognitive impairment or no cognitive impairment and observational tools such as Pain Assessment In Advanced Dementia Scale (PAINAD) for patients with moderate or severe cognitive impairment. Mood was evaluated through the Cornell Scale for Depression in Dementia (CSDD) while behavioral problems were assessed through the Cohen-Mansfield Agitation Inventory (CMAI) and Neuropsychiatric Inventory (NPI). Results: Only 42.5% of patients evaluated by NRS provided a reliable answer; of these, 20.4% reported no pain. The percentage of pain evaluated by PAINAD was 51.8% . Analysis of data showed a statistically significant correlation between diagnosis of pain and depressive symptoms, assessed with CSDD (p  = 0.0113), as well as by single items of NPI, such as anxiety (p  = 0.0362) and irritability (p  = 0.0034), and F1 profile (Aggression) of CMAI (p  = 0.01). Conclusion: This study confirms that self-report alone is not sufficient to assess pain in elderly people with dementia; the observational tool is a necessary and suitable way of assessing pain in patients with cognitive impairment. If not adequately treated, chronic pain can cause depression, agitation, and aggression in patients with dementia. Show more

Keywords: Behavior, dementia, nursing home, pain

DOI: 10.3233/JAD-150808

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1217-1225, 2016

Authors: Bourgade, Karine | Le Page, Aurélie | Bocti, Christian | Witkowski, Jacek M. | Dupuis, Gilles | Frost, Eric H. | Fülöp Jr., Tamás

Article Type: Research Article

Abstract: Senile amyloid plaques are one of the main hallmarks of Alzheimer’s disease (AD). They correspond to insoluble deposits of amyloid-β peptides (Aβ) and are responsible for the inflammatory response and neurodegeneration that lead to loss of memory. Recent data suggest that Aβ possess antimicrobial and anti-viral activity in vitro . Here, we have used cocultures of neuroglioma (H4) and glioblastoma (U118-MG) cells as a minimal in vitro model to investigate whether Aβ is produced by neuroglioma cells and whether this could result in protective anti-viral activity against HSV-1 infection. Results showed that H4 cells secreted Aβ42 in response …to HSV-1 challenge and that U118-MG cells could rapidly internalize Aβ42 . Production of pro-inflammatory cytokines TNFα and IL-1β by H4 and U118-MG cells occurred under basal conditions but infection of the cells with HSV-1 did not significantly upregulate production. Both cell lines produced low levels of IFNα . However, extraneous Aβ42 induced strong production of these cytokines. A combination of Aβ42 and HSV-1 induced production of pro-inflammatory cytokines TNFα and IL-1β, and IFNα in the cell lines. The reported anti-viral protection of Aβ42 was revealed in transfer experiments involving conditioned medium (CM) of HSV-1-infected H4 cells. CM conferred Aβ-dependent protection against HSV-1 replication in de novo cultures of H4 cells challenged with HSV-1. Type 1 interferons did not play a role in these assays. Our data established that H4 neuroglioma cells produced Aβ42 in response to HSV-1 infection thus inhibiting secondary replication. This mechanism may play a role in the etiology of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, cocultures, glial cells, herpes simplex virus-1 (HSV-1), neuronal cells, viral replication inhibition

DOI: 10.3233/JAD-150652

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1227-1241, 2016

Authors: Ni, Ling | Liu, Renyuan | Yin, Zhenyu | Zhao, Hui | Nedelska, Zuzana | Hort, Jakub | Zhou, Fei | Wu, Wenbo | Zhang, Xin | Li, Ming | Yu, Haiping | Zhu, Bin | Xu, Yun | Zhang, Bing

Article Type: Research Article

Abstract: Background: Lacunar infarctions (LI) have been associated with a cognitive decline and an increased risk of dementia. Whether and how the pattern of spontaneous brain activity in patients with mild cognitive impairment (MCI) differs in subjects with and without concomitant LI remains unclear. Objective: To compare the pattern of spontaneous brain activity in MCI patients with versus those without LI using resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Forty-eight MCI patients, including 22 with LI [MCI-LI] and 26 without LI [MCI-no LI], and 28 cognitive normal subjects underwent rs-fMRI post-processed using regional homogeneity (ReHo) and the …amplitude of low-frequency fluctuation (ALFF) methods. Results: Compared with cognitively normal subjects, the MCI-LI patients had decreased ReHo in the precuneus/cuneus (Pcu/CU) and insula; decreased ALFF in the Pcu/CU and frontal lobe; and increased ALFF and ReHo in the temporal lobe. While the MCI-no LI group had increased ReHo and ALFF in the bilateral hippocampus and parahippocampal gyrus, frontal lobe, and decreased ALFF and ReHo in the temporal lobe. Compared with the MCI-no LI patients, those with MCI-LI had decreased ALFF in the frontal lobe; decreased ReHo in the Pcu/CU and insula; and increased ALFF and ReHo in the temporal lobe (p  <  0.05, AlphaSim corrected). In MCI-LI patients, the MOCA scores showed a relatively weak correlation with ALFF values in the medial frontal gyrus (r  = 0.432, p  = 0.045) (of borderline significance after Bonferroni correction). Conclusions: The spontaneous brain activities in MCI-LI were distinct from MCI-no LI. The probable compensatory mechanism observed in MCI-no LI might be disrupted in MCI with LI due to vascular damage. Show more

Keywords: Amplitude of low-frequency fluctuation, lacunar infarction, mild cognitive impairment, regional homogeneity

DOI: 10.3233/JAD-150622

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1243-1254, 2016

Authors: Villa, Alessandro

Article Type: Book Review

DOI: 10.3233/JAD-160030

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1255-1256, 2016

Article Type: Other

DOI: 10.3233/JAD-151138

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1257-1261, 2016

Article Type: Other

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1263-1275, 2016