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