Journal of Alzheimer's Disease - Volume 52, issue 4

Authors: Li, Xinyi | Song, Yuanli | Sanders, Charles R. | Buxbaum, Joel N.

Article Type: Research Article

Abstract: In Alzheimer’s disease (AD), most hippocampal and cortical neurons show increased staining with anti-transthyretin (TTR) antibodies. Genetically programmed overexpression of wild type human TTR suppressed the neuropathologic and behavioral abnormalities in APP23 AD model mice and TTR-Aβ complexes have been isolated from some human AD brains and those of APP23 transgenic mice. In the present study, in vitro NMR analysis showed interaction between the hydrophobic thyroxine binding pocket of TTR and the cytoplasmic loop of the C99 fragment released by β-secretase cleavage of AβPP, with Kd  = 86±9 μM. In cultured cells expressing both proteins, the interaction reduced phosphorylation …of C99 (at T668) and suppressed its cleavage by γ -secretase, significantly decreasing Aβ secretion. Coupled with its previously demonstrated capacity to inhibit Aβ aggregation (with the resultant cytotoxicity in tissue culture) and its regulation by HSF1, these findings indicate that TTR can behave as a stress responsive multimodal suppressor of AD pathogenesis. Show more

Keywords: Alzheimer’s disease, Aβ, AβPP, APP, APP23, gamma secretase, nuclear magnetic resonance, phosphorylation, transthyretin

DOI: 10.3233/JAD-160033

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1263-1275, 2016

Authors: Innes, Kim E. | Selfe, Terry Kit | Khalsa, Dharma Singh | Kandati, Sahiti

Article Type: Research Article

Abstract: Background: Older adults with subjective cognitive decline (SCD) are at increased risk not only for Alzheimer’s disease, but for poor mental health, impaired sleep, and diminished quality of life (QOL), which in turn, contribute to further cognitive decline, highlighting the need for early intervention. Objective: In this randomized controlled trial, we assessed the effects of two 12-week relaxation programs, Kirtan Kriya Meditation (KK) and music listening (ML), on perceived stress, sleep, mood, and health-related QOL in older adults with SCD. Methods: Sixty community-dwelling older adults with SCD were randomized to a KK or ML program …and asked to practice 12 minutes daily for 12 weeks, then at their discretion for the following 3 months. At baseline, 12 weeks, and 26 weeks, perceived stress, mood, psychological well-being, sleep quality, and health-related QOL were measured using well-validated instruments. Results: Fifty-three participants (88%) completed the 6-month study. Participants in both groups showed significant improvement at 12 weeks in psychological well-being and in multiple domains of mood and sleep quality (p ’s≤0.05). Relative to ML, those assigned to KK showed greater gains in perceived stress, mood, psychological well-being, and QOL-Mental Health (p ’s≤0.09). Observed gains were sustained or improved at 6 months, with both groups showing marked and significant improvement in all outcomes. Changes were unrelated to treatment expectancies. Conclusions: Findings suggest that practice of a simple meditation or ML program may improve stress, mood, well-being, sleep, and QOL in adults with SCD, with benefits sustained at 6 months and gains that were particularly pronounced in the KK group. Show more

Keywords: Alzheimer's disease, memory complaints, mind-body therapy, mood, quality of life, sleep, stress, subjective, cognitive impairment

DOI: 10.3233/JAD-151106

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1277-1298, 2016

Authors: Berger, Miles | Nadler, Jacob W. | Friedman, Allan | McDonagh, David L. | Bennett, Ellen R. | Cooter, Mary | Qi, Wenjing | Laskowitz, Daniel T. | Ponnusamy, Vikram | Newman, Mark F. | Shaw, Leslie M. | Warner, David S. | Mathew, Joseph P. | James, Michael L. | MAD-PIA trial team

Collaborators: Radhakrishnan, Senthil | Carter, James | Lad, Shivanandan | Zomorodi, Ali | Sampson, John | Fukushima, Takanori | Adogwa, Owoicho | Clemmons, Karen | Conde, Carlos | Olaleye, Omowunmi | Balajonda, Naraida | Aquino, Jhoanna | Funk, Bonita | Li, Yi-Ju | White, William D.

Article Type: Research Article

Abstract: Background: Preclinical studies have found differential effects of isoflurane and propofol on the Alzheimer’s disease (AD)-associated markers tau, phosphorylated tau (p-tau) and amyloid-β (Aβ). Objective: We asked whether isoflurane and propofol have differential effects on the tau/Aβ ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers. Methods: Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n  = 21) or propofol (n  = 18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and …examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time. Results: The CSF tau/Aβ ratio did not differ between isoflurane- versus propofol-treated patients (p  = 1.000). CSF tau/Aβ ratio and tau levels increased 10 and 24 h after drain placement (p  = 2.002×10–6 and p  = 1.985×10–6 , respectively), mean CSF p-tau levels decreased (p  = 0.005), and Aβ levels did not change (p  = 0.152). There was no interaction between anesthetic treatment and time for any of these biomarkers. None of the examined genetic polymorphisms, including ApoE4 , were associated with tau increase (n  = 9 polymorphisms, p  > 0.05 for all associations). Conclusion: Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aβ ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aβ ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations. Show more

Keywords: Amyloid-beta, anesthesia, cerebrospinal fluid, isoflurane, propofol, surgery, tau protein

DOI: 10.3233/JAD-151190

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1299-1310, 2016

Authors: Zhai, Yun | Yamashita, Toru | Nakano, Yumiko | Sun, Zhuoran | Morihara, Ryuta | Fukui, Yusuke | Ohta, Yasuyuki | Hishikawa, Nozomi | Abe, Koji

Article Type: Research Article

Abstract: A rapidly progressing aging society has raised attention to white matter lesions in Alzheimer’s disease. In the present study, we applied an AD plus cerebral hypoperfusion (HP) mouse model and investigated the alternation of key protein molecules in the nodal, paranodal, and intermodal sites in the white matter as well as the efficacy of galantamine. Cerebral HP was induced in APP23 mice by bilateral common carotid arteries stenosis with ameroid constrictors. Compared with the wild type and simple APP23 mice, APP23 + HP mice showed a progressive loss of MAG and NF186 from 6 to 12 months, broken misdistribution of …MBP, and extended relocation of Nav 1.6 and AnkG beyond the primary nodal region in the corpus callosum. Such abnormal neuropathological processes were retrieved with galantamine treatment. The present study demonstrated that cerebral HP strongly disrupted white matter integrity (WMI) at intermodal, paranodal, and Ranvier’s nodal sites which may be associated with cognitive decline. Galantamine treatment significantly protected such WMI probably by allosterically potentiating ligand action. Show more

Keywords: Alzheimer’s disease, APP23 mice, galantamine, hypoperfusion, white matter mater lesion

DOI: 10.3233/JAD-160120

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1311-1319, 2016

Authors: Müller, Mareike | Kuiperij, H. Bea | Versleijen, Alexandra A.M. | Chiasserini, Davide | Farotti, Lucia | Baschieri, Francesca | Parnetti, Lucilla | Struyfs, Hanne | De Roeck, Naomi | Luyckx, Jill | Engelborghs, Sebastiaan | Claassen, Jurgen A. | Verbeek, Marcel M.

Article Type: Research Article

Abstract: MicroRNAs (miRNAs) regulate translational inhibition of proteins, but are also detected in body fluids, including cerebrospinal fluid (CSF), where they may serve as disease-specific biomarkers. Previously, we showed differential expression of miR-146a, miR-29a, and miR-125b in the CSF of Alzheimer’s disease (AD) patients versus controls. In this study, we aim to confirm these findings by using larger, independent sample cohorts of AD patients and controls from three different centers. Furthermore, we aim to identify confounding factors that possibly arise using such a multicenter approach. The study was extended by including patients diagnosed with mild cognitive impairment due to AD, frontotemporal …dementia and dementia with Lewy bodies. Previous results of decreased miR-146a levels in AD patients compared to controls were confirmed in one center. When samples from all three centers were combined, several confounding factors were identified. After controlling for these factors, we did not identify differences in miRNA levels between the different groups. However, we provide suggestions to circumvent various pitfalls when measuring miRNAs in CSF to improve future studies. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, frontotemporal dementia, Lewy body disease, microRNAs, mild cognitive impairment

DOI: 10.3233/JAD-160038

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1321-1333, 2016

Authors: Beheshti, Iman | Olya, Hossain G.T. | Demirel, Hasan | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Recently, automatic risk assessment methods have been a target for the detection of Alzheimer’s disease (AD) risk. Objective: This study aims to develop an automatic computer-aided AD diagnosis technique for risk assessment of AD using information diffusion theory. Methods: Information diffusion is a fuzzy mathematics logic of set-value that is used for risk assessment of natural phenomena, which attaches fuzziness (uncertainty) and incompleteness. Data were obtained from voxel-based morphometry analysis of structural magnetic resonance imaging. Results and Conclusion: The information diffusion model results revealed that the risk of AD increases with a …reduction of the normalized gray matter ratio (p  > 0.5, normalized gray matter ratio <40%). The information diffusion model results were evaluated by calculation of the correlation of two traditional risk assessments of AD, the Mini-Mental State Examination and the Clinical Dementia Rating. The correlation results revealed that the information diffusion model findings were in line with Mini-Mental State Examination and Clinical Dementia Rating results. Application of information diffusion model contributes to the computerization of risk assessment of AD, which has a practical implication for the early detection of AD. Show more

Keywords: Alzheimer’s disease, computer-aided AD diagnosis, early detection, gray matter volume, information diffusion theory, risk assessment

DOI: 10.3233/JAD-151176

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1335-1342, 2016

Authors: Iyappan, Anandhi | Gündel, Michaela | Shahid, Mohammad | Wang, Jiali | Li, Hui | Mevissen, Heinz-Theodor | Müller, Bernd | Fluck, Juliane | Jirsa, Viktor | Domide, Lia | Younesi, Erfan | Hofmann-Apitius, Martin

Article Type: Research Article

Abstract: Molecular signaling pathways have been long used to demonstrate interactions among upstream causal molecules and downstream biological effects. They show the signal flow between cell compartments, the majority of which are represented as cartoons. These are often drawn manually by scanning through the literature, which is time-consuming, static, and non-interoperable. Moreover, these pathways are often devoid of context (condition and tissue) and biased toward certain disease conditions. Mining the scientific literature creates new possibilities to retrieve pathway information at higher contextual resolution and specificity. To address this challenge, we have created a pathway terminology system by combining signaling pathways and …biological events to ensure a broad coverage of the entire pathway knowledge domain. This terminology was applied to mining biomedical papers and patents about neurodegenerative diseases with focus on Alzheimer’s disease. We demonstrate the power of our approach by mapping literature-derived signaling pathways onto their corresponding anatomical regions in the human brain under healthy and Alzheimer’s disease states. We demonstrate how this knowledge resource can be used to identify a putative mechanism explaining the mode-of-action of the approved drug Rasagiline, and show how this resource can be used for fingerprinting patents to support the discovery of pathway knowledge for Alzheimer’s disease. Finally, we propose that based on next-generation cause-and-effect pathway models, a dedicated inventory of computer-processable pathway models specific to neurodegenerative diseases can be established, which hopefully accelerates context-specific enrichment analysis of experimental data with higher resolution and richer annotations. Show more

Keywords: Alzheimer’s disease, disease mechanism, disease modeling, neurodegeneration, pathway terminology

DOI: 10.3233/JAD-151178

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1343-1360, 2016

Authors: Bier, Nathalie | Belchior, Patricia da Cunha | Paquette, Guillaume | Beauchemin, Émilie | Lacasse-Champagne, Ariane | Messier, Chantal | Pellerin, Marie-Line | Petit, Marisol | Mioshi, Eneida | Bottari, Carolina

Article Type: Research Article

Abstract: Background: Dysfunctions in complex activities of daily living (ADLs) are a normal part of the aging process. However, differentiating functional decline associated with healthy aging from the subtle decline experienced by individuals with mild cognitive impairment and early dementia constitutes a challenge. Finding an appropriate tool that can capture these subtle but important functional changes represents a priority. Objectives: The aims of this study were to evaluate the feasibility of using the Instrumental Activities of Daily Living Profile (IADL Profile) with elderly participants and to describe their level of difficulty encountered in each task. Methods: …The tool was administered to a group of 40 elderly participants living in the community. Results: The IADL Profile was found to be feasible to use in older individuals; the tool also showed sensitivity to the difficulties experienced by this population in everyday functioning. Conclusion: The IADL Profile is a promising ecological tool to evaluate independence in aging and may help to identify individuals with MCI. This tool may also contribute to the development of tailored interventions to enhance everyday functioning in the older population. Show more

Keywords: Activities of daily living, aging, executive functions, independence

DOI: 10.3233/JAD-150957

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1361-1371, 2016

Authors: Hoscheidt, Siobhan M. | Starks, Erika J. | Oh, Jennifer M. | Zetterberg, Henrik | Blennow, Kaj | Krause, Rachel A. | Gleason, Carey E. | Puglielli, Luigi | Atwood, Craig S. | Carlsson, Cynthia M. | Asthana, Sanjay | Johnson, Sterling C. | Bendlin, Barbara B.

Article Type: Research Article

Abstract: Background: Type 2 diabetes is associated with an increased risk for Alzheimer’s disease (AD). Regulation of normal insulin function may be important in reducing the prevalence of dementia due to AD, particularly in individuals who harbor genetic risk for or have a parental family history of AD. The relationship between insulin resistance (IR) and AD pathology remains poorly understood, particularly in midlife prior to the onset of clinical metabolic disease or cognitive decline. Objective: We examined associations between IR as indexed by HOMA-IR, cerebrospinal fluid (CSF) biomarkers of AD pathology, and memory in middle-aged adults enriched for …AD. We postulated that higher HOMA-IR and APOE ɛ 4 carriage would be associated with greater CSF AD pathology and poor memory performance. Methods: Cognitively asymptomatic middle-aged adults (N  = 70, mean age = 57.7 years) from the Wisconsin Alzheimer’s Disease Research Center with a parental family history of dementia due to AD underwent lumbar puncture, blood draw, and neuropsychological testing. CSF AD biomarkers including soluble amyloid-β protein precursor β (sAβPPβ), amyloid-β42 (Aβ42 ), and phosphorylated tau (P-tau181 ) were examined with respect to HOMA-IR and APOE ɛ 4 status. Delayed memory performance was examined with respect to HOMA-IR, CSF AD biomarkers, and APOE ɛ 4 status. Results: Higher HOMA-IR was associated with higher sAβPPβ and Aβ42 .  APOE ɛ 4 carriers had significantly higher levels of sAβPPα , sAβPPβ, and P-tau181 /Aβ42 compared to noncarriers. The concurrent presence of higher HOMA-IR and CSF AD pathology predicted worse delayed memory performance. Conclusion: Overall, the findings suggest that IR and APOE ɛ 4 are contributing factors to the development of AD pathology in midlife, and provide support for targeting insulin function as a potentially modifiable risk factor for AD. Show more

Keywords: APOE ɛ4, CSF AD biomarkers, insulin resistance, memory function

DOI: 10.3233/JAD-160110

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1373-1383, 2016

Authors: Ota, Kenichi | Oishi, Naoya | Ito, Kengo | Fukuyama, Hidenao | and SEAD-J Study Group | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Prediction of progression to Alzheimer’s disease (AD) in amnestic mild cognitive impairment (MCI) is challenging because of its heterogeneity. Objective: To evaluate a stratification method on different cohorts and to investigate whether stratification in amnestic MCI could improve prediction accuracy. Methods: We identified 80 and 79 patients with amnestic MCI from different cohorts, respectively. They underwent baseline magnetic resonance imaging (MRI) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans. We performed hierarchical clustering with three imaging biomarkers: Brain volume on MRI, left hippocampus grey matter loss on MRI, and left inferior temporal gyrus …glucose hypometabolism on FDG-PET. Regions-of-interest for biomarkers were defined by the Automated Anatomical Labeling atlas. We performed voxel-wise statistical parametric mapping to explore differences between clusters in patterns of grey matter loss and glucose hypometabolism. We compared time to progression using an interval-censored parametric model. We evaluated predictive performance using logistic regression. Results: Similar clusters were found in different cohorts. MCI1 had the healthiest biomarker profile of cognitive performance and imaging biomarkers. MCI2 had cognitive performance and MRI measures intermediate between those of nonconverters and converters. MCI3 showed the severest reduction in brain volume and left hippocampal atrophy. MCI4 showed remarkable glucose hypometabolism in the left inferior temporal gyrus, and also demonstrated significant decreases in most cognitive scores, including non-memory functions. MCI4 showed the highest risk for progression. The prediction of progression of MCI2 especially benefited from the stratification. Conclusion: Stratification with imaging biomarkers in amnestic MCI can be a good approach for improving predictive performance. Show more

Keywords: Alzheimer’s disease, clustering, 18F-FDG, heterogeneity, magnetic resonance imaging, mild cognitive impairment, positron-emission tomography

DOI: 10.3233/JAD-160145

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1385-1401, 2016

Authors: Wang, Min Jeong | Yi, SangHak | Han, Jee-young | Park, So Young | Jang, Jae-Won | Chun, In Kook | Giau, Vo Van | Bagyinszky, Eva | Lim, Kun Taek | Kang, Sung Min | An, Seong Soo A. | Park, Young Ho | Youn, Young Chul | Kim, SangYun

Article Type: Research Article

Abstract: Background: Recently, a Korean research group suggested a consensus protocol, based on the Alzheimer’s Disease Neuroimaging Initiative study protocol but with modifications for minimizing the confounding factors, for the evaluation of cerebrospinal fluid (CSF) biomarkers. Objective: Here, we analyzed fluid and imaging biomarkers of Alzheimer’s disease (AD) in Korean population. We used the updated protocol to propose a more accurate CSF biomarker value for the diagnosis of AD. Methods: Twenty-seven patients with AD and 30 cognitively normal controls (NC) were enrolled. CSF was collected from 55 subjects (patients with AD = 26, NC = 29) following the Korea consensus …protocol. CSF biomarkers were measured using the INNO-BIA AlzBio3 immunoassay, and Pittsburgh compound B (PIB) positron emission tomography (PET) scans were also performed. Results: The cutoff values of CSF amyloid beta 1-42 (Aβ42 ), total tau (t-Tau), and phosphorylated tau (p-Tau) proteins were 357.1 pg/ml, 83.35 pg/ml, and 38.00 pg/ml, respectively. The cutoff values of CSF t-Tau/Aβ42 and p-Tau/Aβ42 ratio- were 0.210 (sensitivity 100%, specificity 86.21%) and 0.1350 (sensitivity 88.46%, specificity of 92.86%). The concordance rate with PIB-PET was higher using the CSF t-Tau/Aβ42 ratio (κ = 0.849, CI 0.71–0.99) than CSF Aβ42 alone (κ = 0.703, CI 0.51–0.89). Conclusions: Here, we improved controversial factors associated with the previous CSF study protocol and suggested a new cutoff value for the diagnosis of AD. Our results showed good diagnostic performance for differentiation of AD. Thus, we expect our findings could be a cornerstone in the establishment and clinical application of biomarkers for AD diagnosis. Show more

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, diagnosis, Pittsburgh compound B, protocol

DOI: 10.3233/JAD-160143

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1403-1413, 2016

Authors: Beydoun, May A. | Canas, Jose-Atilio | Dore, Gregory A. | Beydoun, Hind A. | Rostant, Ola S. | Fanelli-Kuczmarski, Marie T. | Evans, Michele K. | Zonderman, Alan B.

Article Type: Research Article

Abstract: Uric acid, a waste metabolite among humans, was linked to various cognitive outcomes. We describe sex and age-group specific associations of baseline serum uric acid (SUAbase ) and significant change in SUA (ΔSUA: 1 versus 0 = decrease versus no change; 2 versus 0 = increase versus no change) with longitudinal annual rate of cognitive change among a large sample of urban adults. Data from the Healthy Aging in Neighborhoods of Diversity across the Life Span study, 2004–2009 (visit 1) and 2009–2013 (visit 2) were used. Of 3,720 adults selected at baseline (age range: 30–64 y), complete data were available for N  = 1,487–1,602 with …a mean repeat of 1.5–1.7 visits/participant. Cognitive test domains spanned attention, processing speed, learning/memory, executive function, visuo-spatial/visuo-construction ability, language/verbal, and global cognitive function. SUA was measured at both visits. Multiple mixed-effects regression analyses were conducted. In the total population, a higher SUAbase was associated with a faster annual rate of decline on a measure of visual memory/visuo-construction ability (the Benton Visual Retention Test) by γ = 0.07 with a standard error of 0.02, p  < 0.001. Among older men, a significant increase in SUA was associated with slower decline on a test of attention/processing speed, namely Trailmaking test, Part A, measured in seconds to completion (γ = –6.91 ± 1.73, p  < 0.001). In sum, a higher SUAbase was associated with faster cognitive decline over-time in a visual memory/visuo-construction ability test. ΔSUA had particular beneficial effects of an increasing ΔSUA on the domain of attention/processing speed among older men. More longitudinal studies are needed to examine cognitive domain-specific effects of over-time change in SUA within sex and age groups. Show more

Keywords: Aging, cognition, serum uric acid, sex differences

DOI: 10.3233/JAD-160028

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1415-1430, 2016

Authors: Shindler-Itskovitch, Tali | Ravona-Springer, Ramit | Leibovitz, Arthur | Muhsen, Khitam

Article Type: Research Article

Abstract: Background: A positive association between Helicobacter pylori infection and dementia has been reported, yet findings are inconsistent. Objective: To examine the association between H. pylori infection and dementia. Methods: A literature search was performed using the databases OVID-Medline, Institute of Scientific Information Web of Science, and EMBASE. The meta-analysis was conducted using the random effects model. The primary analysis included studies in which the exposure variable was presence of H. pylori infection (yes versus no) and the outcome was incident dementia (yes versus no), which was pre-selected as the end-result of gradual …cognitive decline overtime. Publication bias was explored using funnel plot and the Egger regression intercept. Results: A total of 260 records were identified; 13 addressed cognition and/or dementia in relation to H. pylori infection, of which only seven were included in the meta-analysis. The primary analysis showed a significant positive association between H. pylori infection and dementia; pooled odds ratio 1.71 (95% CI 1.17–2.49) (pv  = 0.01). No significant evidence of publication bias was found. Conclusions: H. pylori may play a role in the etiology of dementia. Identification of the biological mechanisms of such association is needed, as well as assessment of the impact of H. pylori therapy on the risk and progression of dementia. Show more

Keywords: Alzheimer’s disease, cognition, dementia, Helicobacter pylori infection, meta-analysis

DOI: 10.3233/JAD-160132

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1431-1442, 2016

Authors: Teipel, Stefan | Grothe, Michel J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Smoking has been found associated with decreased cerebral volumes in healthy adults and in various neuropsychiatric disorders. Objective: We aimed to determine whether chronic nicotine exposure through smoking is associated with reduced volume of cortically projecting cholinergic basal forebrain nuclei in healthy aging, mild cognitive impairment (MCI), and dementia stages of Alzheimer’s disease (AD). Methods: We retrieved cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database including 179 cognitively normal elderly subjects, 270 subjects with early stage MCI, 136 subjects in later, more advanced, stage of MCI, and 86 subjects in dementia stages …of AD. We determined the association between past or current smoking versus lifetime non-smoker status on the volumes of the basal forebrain determined from volumetric MRI scans. Hippocampus volume was used as a control region. Significant effects were controlled for mediating or moderating effects of respiratory and cardiovascular morbidity. Results: In cognitively healthy individuals and early MCI, past or current smoking was significantly associated with smaller basal forebrain volume. This effect was independent from age, sex, or cardiovascular or respiratory morbidity. Hippocampus volume was not associated with smoking. In late MCI and AD dementia, smoking was not associated with basal forebrain or hippocampus volumes. Conclusions: Our findings suggest that chronic nicotine exposure through smoking may lead to atrophy of cholinergic input areas of the basal forebrain. This effect may account for an increased risk of AD dementia onset with smoking by exhausting the cholinergic system reserve capacity. Show more

Keywords: Aging, cholinergic system, hippocampus, magnetic resonance imaging, nicotine

DOI: 10.3233/JAD-151100

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1443-1451, 2016

Authors: Waragai, Masaaki | Adame, Anthony | Trinh, Ivy | Sekiyama, Kazunari | Takamatsu, Yoshiki | Une, Kaori | Masliah, Eliezer | Hashimoto, Makoto

Article Type: Research Article

Abstract: Adiponectin (APN) is protective in animal models of neurodegenerative diseases, but the role of APN in human brain has not been established. Using an enzyme-linked immunosorbent assay, we found that APN was significantly decreased in cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD), compared to those in patients with mild cognitive impairment (MCI) and in normal controls (NC), despite elevation of APN in serum of patients with MCI and AD compared to that in NC. The discrepancy of CSF APN from serum APN in AD may suggest some critical actions of APN in the pathogenesis of AD. Indeed, it …was histologically observed that APN was co-localized with tau in neurofibrillary tangles and immunoblot analysis showed that the functional trimers of APN were significantly decreased in AD compared to those in NC. Collectively, a loss of function of APN may be involved in the pathogenesis of AD. Show more

Keywords: Adiponectin, Alzheimer’s disease, cerebrospinal fluid, neurofibrillary tangles, sequestration, serum, tau

DOI: 10.3233/JAD-151116

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1453-1459, 2016

Authors: Han, Pengcheng | Shi, Jiong

Article Type: Research Article

Abstract: Amyloid plaques and Tau protein neurofibrillary tangles are considered the two most important pathogenic factors in Alzheimer’s disease. The prevailing amyloid cascade hypothesis suggests that amyloid-β (Aβ) elevation induces downstream Tau hyperphosphorylation and aggregation, synaptic dysfunction, and neuronal loss that ultimately results in cognitive impairment. Alternatively, the dual-pathway hypothesis suggests that Aβ and abnormal Tau are two independent factors that exert synergistic effects on synaptic dysfunction and neuronal loss. We hypothesize that the intrinsic interaction of Aβ and Tau would better predict cognitive impairment. Herein, we propose an Aβ-Tau interactive model based on a review of the medical literature, mathematic …modeling, and analysis of our clinicopathological data. Show more

Keywords: Alzheimer’s disease, amyloid plaque, neurofibrillary tangle, Tau

DOI: 10.3233/JAD-151206

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1461-1470, 2016

Authors: Fernandez, Ana M. | Hervas, Ruben | Dominguez-Fraile, Manuel | Garrido, Victoria Navarro | Gomez-Gutierrez, Patricia | Vega, Miguel | Vitorica, Javier | Perez, Juan J. | Torres Aleman, Ignacio

Article Type: Research Article

Abstract: Astrocytes actively participate in neuro-inflammatory processes associated to Alzheimer’s disease (AD), and other brain pathologies. We recently showed that an astrocyte-specific intracellular signaling pathway involving an interaction of the phosphatase calcineurin with the transcription factor FOXO3 is a major driver in AD-associated pathological inflammation, suggesting a potential new druggable target for this devastating disease. We have now developed decoy molecules to interfere with calcineurin/FOXO3 interactions, and tested them in astrocytes and neuronal co-cultures exposed to amyloid-β (Aβ) toxicity. We observed that interference of calcineurin/FOXO3 interactions exerts a protective action against Aβ-induced neuronal death and favors the production of a set …of growth factors that we hypothesize form part of a cytoprotective pathway to resolve inflammation. Furthermore, interference of the Aβ-induced interaction of calcineurin with FOXO3 by decoy compounds significantly decreased amyloid-β protein precursor (AβPP) synthesis, reduced the AβPP amyloidogenic pathway, resulting in lower Aβ levels, and blocked the expression of pro-inflammatory cytokines TNFα and IL-6 in astrocytes. Collectively, these data indicate that interrupting pro-inflammatory calcineurin/FOXO3 interactions in astrocytes triggered by Aβ accumulation in brain may constitute an effective new therapeutic approach in AD. Future studies with intranasal delivery, or brain barrier permeable decoy compounds, are warranted. Show more

Keywords: Alzheimer’s disease, astrocytes, calcineurin, decoy compounds, FOXO

DOI: 10.3233/JAD-160149

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1471-1478, 2016

Authors: Cestari, José Augusto Ferrari | Fabri, Gisele Maria Campos | Kalil, Jorge | Nitrini, Ricardo | Jacob-Filho, Wilson | de Siqueira, José Tadeu Tesseroli | Siqueira, Silvia Regina D.T.

Article Type: Research Article

Abstract: Background: Oral infections are prevalent in the adult population. Their impact includes the implication as a risk factor for Alzheimer’s disease (AD), altering its progression. One of the potential mechanisms involves immune mediators such as circulating cytokines. Objective: The goal of the present study was to investigate the prevalence of oral infections and blood levels of IL-1β, TNF-α , and IL-6 in patients with AD, mild cognitive impairment (MCI), and controls. Methods: Sixty-five elderly were evaluated (25 AD, 19 MCI, and 21 controls) by the following methods: Mini Mental State Exam, Questionnaire of Functional Activities, …periodontal and oral evaluation, and blood concentrations of IL-1β, TNF-α and IL-6. Results: Patients with AD had high serum IL-6 levels (p  = 0.029), and patients with periodontitis had high serum TNF-α levels (p  = 0.005). There was an association between IL-6 and TNF-α in patients with AD/MCI and periodontitis (p  = 0.023). Conclusion: The increased levels of TNF-α and IL-6 in this study suggests their implication in the overlapping mechanisms between oral infections and AD. Longitudinal studies are necessary for further investigation. Show more

Keywords: Alzheimer’s disease, IL-6, inflammation, mild cognitive impairment, oral infection, periodontitis, TNF-α

DOI: 10.3233/JAD-160212

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1479-1485, 2016

Authors: Ramos-Goicoa, Marta | Galdo-Álvarez, Santiago | Díaz, Fernando | Zurrón, Montserrat

Article Type: Research Article

Abstract: Event-related potentials (ERPs) were recorded from 84 adults (51 to 87 years old) with the aim of exploring the effects of aging (middle-aged and older groups) and cognitive status (healthy or with amnestic mild cognitive impairment, aMCI) on the neural functioning associated with stimulus and response processing in a Stroop color-word task. An interference (or Stroop) effect was observed in the Reaction Time (RT), and the RT and number of errors results were consistent with the age-related decline in performance. Cognitive status did not affect the behavioral performance of the task, but age and cognitive status affected several ERP parameters. …Aging was associated with a) slowing of the neural processing of the stimuli (P150, N2, and P3b latencies were longer), b) greater activation of the motor cortex for response preparation (LRP-R amplitude was larger), and c) use of more neural resources for cognitive control of stimuli (N2 amplitude was larger to the congruent and incongruent stimuli than to the colored X-strings, in the older group). Independent of age, aMCI dedicated more neural resources to processing the irrelevant dimension of the stimulus (they showed a greater difference than the control participants between the P3b amplitude to the colored X-strings and to the congruent/incongruent stimuli) and showed a deficit in the selection and preparation of the motor response (with smaller LRP-S and LRP-R amplitudes). Furthermore, the middle-aged aMCI participants evaluated and classified both congruent and incongruent stimuli more slowly (they showed longer P3b latencies) relative to middle-aged controls. Show more

Keywords: Aging, event-related potentials, mild cognitive impairment, Stroop task

DOI: 10.3233/JAD-151031

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1487-1501, 2016

Authors: Barry, Heather E. | Cooper, Janine A. | Ryan, Cristín | Passmore, A. Peter | Robinson, A. Louise | Molloy, Gerard J. | Darcy, Carmel M. | Buchanan, Hilary | Hughes, Carmel M.

Article Type: Research Article

Abstract: Background: Little is known about prescribing appropriateness for community-dwelling people with dementia (PWD). Objective: To estimate potentially inappropriate prescribing (PIP) prevalence among PWD in primary care in Northern Ireland, and to investigate associations between PIP, polypharmacy, age, and gender. Methods: A retrospective cross-sectional study was conducted, using data from the Enhanced Prescribing Database. Patients were eligible if a medicine indicated for dementia management was dispensed to them during 1 January 2013–31 December 2013. Polypharmacy was indicated by use of ≥4 repeat medications from different drug groups. A subset of the Screening Tool of Older Persons …Potentially Inappropriate Prescriptions (STOPP) criteria, comprising 36 indicators, was applied to the dataset. Overall prevalence of PIP and the prevalence per each STOPP criterion was calculated as a proportion of all eligible persons in the dataset. Logistic regression was used to investigate associations between PIP, polypharmacy, age, and gender. Results: The study population comprised 6826 patients. Polypharmacy was observed in 81.5% (n  = 5564) of patients. PIP prevalence during the study period was 64.4% (95% CI 63.2– 65.5; n  = 4393). The most common instance of PIP was the use of anticholinergic/antimuscarinic medications (25.2%; 95% CI 24.2–26.2; n  = 1718). In multivariable analyses, both polypharmacy and gender (being female) were associated with PIP, with odds ratios of 7.6 (95% CI 6.6–8.7) and 1.3 (95% CI 1.2–1.4), respectively. No association was observed between PIP and age, after adjustments for gender and polypharmacy. Conclusion: This study identified a high prevalence of PIP in community-dwelling PWD. Future interventions may need to focus on certain therapeutic categories and polypharmacy. Show more

Keywords: Dementia, inappropriate prescribing, pharmacoepidemiology, polypharmacy, primary health care

DOI: 10.3233/JAD-151177

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1503-1513, 2016

Article Type: Other

DOI: 10.3233/JAD-160352

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1515-1519, 2016

Article Type: Other

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1521-1537, 2016