Journal of Alzheimer's Disease - Volume 63, issue 2

Authors: Radko, Sergey P. | Khmeleva, Svetlana A. | Mantsyzov, Alexey B. | Kiseleva, Yana Y. | Mitkevich, Vladimir A. | Kozin, Sergey A. | Makarov, Alexander A.

Article Type: Research Article

Abstract: Zinc-induced aggregation of amyloid-β peptides (Aβ) is considered to contribute to the pathogenesis of Alzheimer’s disease. While glycosaminoglycans (GAGs) that are commonly present in interneuronal space are known to enhance Aβ self-aggregation in vitro , the impact of GAGs on the formation of zinc-induced amorphous Aβ aggregates has not yet been thoroughly studied. Here, employing dynamic light scattering, bis-ANS fluorimetry, and sedimentation assays, we demonstrate that heparin serving as a representative GAG modulates the kinetics of zinc-induced Aβ42 aggregation in vitro by slowing the rate of aggregate formation and aggregate size growth. By using synthetic Aβ16 peptides …to model the Aβ metal-binding domain (MBD), heparin was found to effectively interact with MBDs in complex with zinc ions. We suggest that heparin adsorbs to the surface of growing zinc-induced Aβ42 aggregates via electrostatic interactions, thus creating a steric hindrance that inhibits further inclusion of monomeric and/or oligomeric zinc-Aβ42 complexes. Furthermore, the adsorbed heparin can interfere with the zinc-bridging mechanism of Aβ42 aggregation, requiring the formation of two zinc-mediated interaction interfaces in the MBD. As revealed by computer simulations of the zinc-Aβ16 homodimer complexed with a heparin chain, heparin can interact with the MBD via polar contacts with residues Arg-5 and Tyr-10, resulting in a conformational rearrangement that hampers the formation of the second zinc-mediated interaction in the MBD interface. The findings of this study suggest that GAGs, which are common in the in vivo macromolecular environment, may have a substantial impact on the time course of zinc-induced Aβ aggregation. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, aggregation, zinc, heparin

DOI: 10.3233/JAD-171120

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 539-550, 2018

Authors: Zhu, Aiqin | Wu, Zhou | Zhong, Xin | Ni, Junjun | Li, Yinglan | Meng, Jie | Du, Can | Zhao, Xue | Nakanishi, Hiroshi | Wu, Shizheng

Article Type: Research Article

Abstract: Background: Systemic inflammation is known as a risk factor of cognitive decline. Objective: To investigate the effects of propolis on cognitive decline and systemic inflammation in elderly people living at high altitude. Methods: Sixty participants (average 72.8 years) living at altitude (2,260 meters) were randomized to receive propolis (0.83 g, n  = 30) or placebo (n  = 30) for 24 months. Cognitive outcomes were assessed using MMSE and serum cytokine levels were measured for 24 months in a double-blind study. Results: MMSE scores were 26.17 at baseline and 23.87 at 24 months in placebo group. Compared to …placebo group, improvements of MMSE scores were significant in propolis-treated subjects (p  = 0.007) with a response emerging over time (time points×group interaction, p  = 0.016). In addition, the serum IL-1β and IL-6 levels were significantly different across treatments (p  < 0.0001) showing upward and downward trends in placebo- and propolis-treated subjects, respectively (p  < 0.0001). Serum levels of TNF-α were not significantly different across treatment (p  = 0.0528) but with a response emerging over time (time points×group interaction, p  = 0.016). In contrast, serum levels of TGFβ 1 were significantly different across treatments (p  < 0.0001) showing downward and upward trends in placebo- and propolis-treated subjects, respectively. Serum levels of IL-10 were significant for the effect of groups (p  = 0.0411). Furthermore, MMSE scores correlated with the decrease in IL-1β and the increase in TGFβ 1 in serum. Conclusion: Elderly people living at high altitude developed to MCI in 24 months with exacerbation of systemic inflammation. Ingestion of propolis (>12 months) protected against cognitive decline after systemic inflammation was reduced. Show more

Keywords: Alzheimer’s disease, Brazilian green propolis, cognitive function, microglia, mild cognitive impairment, neuroinflammation, neuron, oxidative stress, systemic inflammation

DOI: 10.3233/JAD-170630

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 551-560, 2018

Authors: Makovac, Elena | Serra, Laura | Di Domenico, Carlotta | Marra, Camillo | Caltagirone, Carlo | Cercignani, Mara | Bozzali, Marco

Article Type: Research Article

Abstract: Patients with amnestic mild cognitive impairment (aMCI) have higher probability to develop Alzheimer’s disease (AD) than elderly controls. The detection of subtle changes in brain structure associated with disease progression and the development of tools to identify patients at high risk for dementia in a short time is crucial. Here, we used probabilistic white matter (WM) tractography to explore microstructural alterations within the main association, limbic, and commissural pathways in aMCI patients who converted to AD after 1 year follow-up (MCIconverters ) and those who remained stable (MCIstable ). Both diffusion tensor imaging (DTI) and quantitative magnetization transfer (qMT) parameters …have been considered for a comprehensive pathophysiological characterization of the WM damage. Overall, tract-specific parameters derived from qMT and DTI at baseline were able to differentiate aMCI patients who converted to AD from those who remained stable in time. In particular, the qMT exchange rate, RMB 0 , of the right uncinate fasciculus was significantly decreased in MCIconverters , whereas fractional anisotropy was significantly decreased in the bilateral superior cingulum in MCIconverters compared to MCIstable . These results confirm the involvement of WM and particularly of association fibers in the progression of AD, highlighting disconnection as a potential mechanism. Show more

Keywords: Diffusion tensor imaging, mild cognitive impairment, probabilistic tractography, quantitative magnetization transfer, white matter

DOI: 10.3233/JAD-170995

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 561-575, 2018

Authors: Meyer, Pierre-François | Savard, Melissa | Poirier, Judes | Labonté, Anne | Rosa-Neto, Pedro | Weitz, Tara M. | Town, Terrence | Breitner, John | for the Alzheimer’s Disease Neuroimaging Initiative | the PREVENT-AD Research Group

Article Type: Research Article

Abstract: Immune mechanisms may be important in the pathogenesis of Alzheimer’s disease (AD). Yet, studies comparing cerebrospinal fluid (CSF) and plasma immune marker levels of healthy and demented individuals have yielded conflicting results. We analyzed CSF from 101 members of the parental history-positive PREVENT-AD cohort of healthy aging adults, and 237 participants without dementia from the initial cohort of the Alzheimer’s Disease Neuroimaging Initiative (ADNI-1). Following recent practice, we used the biomarkers total-tau and amyloid-β1-42 to allocate participants from each study into four stages of AD pathogenesis: Stage 0 (no abnormality), Stage 1 (reduced amyloid-β1-42 ), Stage 2 (reduced …amyloid-β1-42 and increased total-tau), or “Suspected Non-Alzheimer Pathology” (elevated total-tau only). Investigating the PREVENT-AD participants’ CSF assay results for 19 immune/inflammatory markers, we found six that showed a distinct bi-directional relationship with pathogenetic stage. Relative to Stage 0, these were diminished at Stage 1 but strongly increased at Stage 2. Among the ADNI participants (90 healthy controls and 147 with mild cognitive impairment), we found that 23 of 83 available CSF markers also showed this distinct pattern. These results support recent observations that immune activation may become apparent only after the onset of both amyloid and tau pathologies. Unexpectedly, they also suggest that immune marker activity may diminish along with earliest appearance of amyloid-β plaque pathology. These findings may explain discordant results from past studies, and suggest the importance of characterizing the extent of AD pathology when comparing clinical groups. Show more

Keywords: Alzheimer’s disease, biomarkers, inflammation, pathology

DOI: 10.3233/JAD-170887

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 577-590, 2018

Authors: Mengel-From, Jonas | Rønne, Mette E. | Carlsen, Anting L. | Skogstrand, Kristin | Larsen, Lisbeth A. | Tan, Qihua | Christiansen, Lene | Christensen, Kaare | Heegaard, Niels H.H.

Article Type: Research Article

Abstract: We aim to examine if circulating micro-RNA and cytokine levels associate with dementia diagnosis and cognitive scores. To test our hypothesis, we use plasma donated from 48 monozygotic twin pairs in 1997 and 46 micro-RNAs and 10 cytokines were quantified using microfluidic RT-qPCR and multiplex solid-phase immunoassays, respectively. Micro-RNA and cytokine profiling were examined for associations with dementia diagnoses in a longitudinal registry study or with cognitive scores at baseline. Thirty-six micro-RNAs and all cytokines were detected consistently. Micro-RNA profiles associate with diagnoses and cognitive scores at statistically significant levels while cytokine only showed trends pointing at chronic inflammation in …twins having or developing dementia. The most notable findings were decreased miR-106a and miR-210, and increased miR-106b expression in twins with a dementia diagnosis. This pioneering evaluation of micro-RNA and cytokine and dementia diagnosis suggests micro-RNA targets in vasculogenesis, lipoprotein transport, and amyloid precursor protein genes. Show more

Keywords: Aging, Alzheimer’s disease, brain, genetics, neurodegenerative

DOI: 10.3233/JAD-171163

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 591-601, 2018

Authors: Stonnington, Cynthia M. | Chen, Yinghua | Savage, Cary R. | Lee, Wendy | Bauer III, Robert J. | Sharieff, Sameen | Thiyyagura, Pradeep | Alexander, Gene E. | Caselli, Richard J. | Locke, Dona E.C. | Reiman, Eric M. | Chen, Kewei

Article Type: Research Article

Abstract: Background: Brain imaging measurements can provide evidence of possible preclinical Alzheimer’s disease (AD). Their ability to predict individual imminent clinical conversion remains unclear. Objective: To investigate the ability of pre-specified volumetric magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) measurements to predict which cognitively unimpaired older participants would subsequently progress to amnestic mild cognitive impairment (aMCI) within 2 years. Methods: From an apolipoprotein E4 (APOE4) enriched prospective cohort study, 18 participants subsequently progressed to the clinical diagnosis of aMCI or probable AD dementia within 1.8±0.8 years (progressors); 20 participants matched for sex, age, education, …and APOE allele dose remained cognitively unimpaired for at least 4 years (nonprogressors). A complementary control group not matched for APOE allele dose included 35 nonprogressors. Groups were compared on baseline FDG-PET and MRI measures known to be preferentially affected in the preclinical and clinical stages of AD and by voxel-wise differences in regional gray matter volume and glucose metabolism. Receiver Operating Characteristic, binary logistic regression, and leave-one-out procedures were used to predict clinical outcome for the a priori measures. Results: Compared to non-progressors and regardless of APOE -matching, progressors had significantly reduced baseline MRI and PET measurements in brain regions preferentially affected by AD and reduced hippocampal volume was the strongest predictor of an individual’s imminent progression to clinically significant memory decline (79% sensitivity/78% specificity among APOE -matched cohorts). Conclusion: Regional MRI and FDG-PET measurements may be useful in predicting imminent progression to clinically significant memory decline. Show more

Keywords: Alzheimer’s disease, magnetic resonance imaging, mild cognitive impairment, positron-emission tomography, prognosis

DOI: 10.3233/JAD-170852

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 603-615, 2018

Authors: Rouch, Isabelle | Pongan, Elodie | Leveque, Yohana | Tillmann, Barbara | Trombert, Béatrice | Getenet, Jean Claude | Auguste, Nicolas | Krolak-Salmon, Pierre | the LACMé group | Laurent, Bernard | Dorey, Jean-Michel

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) mainly occurs in elderly individuals. Comorbidities and chronic pain are frequent in this population. Previous studies revealed that personality modulates both chronic pain (CP) andADoccurrence and evolution. Moreover, as pain treatments can induce side-effects, non-drugs treatments, such as art interventions, are interesting alternative therapies for decreasing CP in these patients. Objective: Our aim was to assess the potential role of personality traits on art intervention efficacy for reducing CP in a population of patients with mild AD. Methods: Design: multicenter randomized controlled trial. Fifty mild AD patients underwent a 12-week art intervention …including singing and painting groups. Personality was assessed with the Big Five Inventory before the sessions. CP was measured with Numeric Rating Scale (NRS) [Usual pain (NRS-U) and most Intense pain (NRS-I)], Simple Visual Scale [Usual pain (SVS-U) and most Intense pain (SVS-I)] and Brief Pain Inventory (BPI) before and after the sessions. The influence of personality traits on CP evolution before and after art intervention was assessed with multiple linear regression models. Results: A positive association was observed between neuroticism and the evolution of three CP measures including NRS-U (B = 0.34, p = 0.01), SVS-U (B = 0.20, p = 0.04), and BPI-U (B = 0.46, p = 0.02) evolution. No significant relationship was observed between neuroticism and NRS-I, SVS-I and BPI-R evolution. Conclusions: Our findings suggest that neuroticism can decrease the efficacy of group art intervention on pain in patients with mild AD. Individual therapies could be more appropriate for these patients. These results emphasize the interest of taking into account patients’ personality before proposing them to participate to a group therapy. Show more

Keywords: Alzheimer’s disease, music, pain, personality

DOI: 10.3233/JAD-170990

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 617-624, 2018

Authors: Andriuta, Daniela | Roussel, Martine | Barbay, Mélanie | Despretz-Wannepain, Sandrine | Godefroy, Olivier | Godefroy and GRECogVASC study group

Collaborators: Godefroy, Olivier | Roussel, Martine | Barbay, Mélanie | Canaple, Sandrine | Lamy, Chantal | Leclercq, Claire | Arnoux, Audrey | Despretz-Wannepain, Sandrine | Despretz, Pascal | Berrissoul, Hassan | Picard, Carl | Diouf, Momar | Loas, Gwénolé | Deramond, Hervé | Taillia, Hervé | Ardisson, Anne-Emmanuelle | Nédélec-Ciceri, Claudine | Bonnin, Camille | Thomas-Anterion, Catherine | Grangette, Francoise | Varvat, Jérome | Quaglino, Véronique | Beaunieux, Hélène | Moroni, Christine | Martens-Chazelles, Audrey | Batier-Monperrus, Stéphanie | Monteleone, Cécile | Costantino, Véronique | Theunssens, Eric

Article Type: Research Article

Abstract: Background: The contrast between memory versus executive function impairments is commonly used to differentiate between neurocognitive disorders (NCDs) due to Alzheimer’s disease (AD) and vascular cognitive impairment (VCI). We reconsidered this question because of the current use of AD biomarkers and the recent revision of the criteria for AD, VCI, and dysexecutive syndrome. Objective: To establish and compare the neuropsychological profiles in AD (i.e., with positive CSF biomarkers) and in VCI. Methods: We included 62 patients with mild or major NCDs due to pure AD (with positive CSF biomarker assays), and 174 patients (from the GRECogVASC …cohort) with pure VCI. The neuropsychological profiles were compared after stratification for disease severity (mild or major NCD). We defined a memory-executive function index (the mean z score for the third free recall and the delayed free recall in the Free and Cued Selective Reminding Test minus the mean z score for category fluency and the completion time in the Trail Making Test part B) and determined its diagnostic accuracy. Results: Compared with VCI patients, patients with AD had significantly greater memory impairments (p  = 0.001). Executive function was impaired to a similar extent in the two groups (p  = 0.11). Behavioral executive disorders were more prominent in the AD group (p  = 0.001). Although the two groups differed significant with regard to the memory-executive function index (p  < 0.001), the latter’s diagnostic accuracy was only moderate (sensitivity: 63%, specificity: 87%). Conclusion: Although the contrast between memory and executive function impairments was supported at the group level it does not reliably discriminate between AD and VCI at the individual level. Show more

Keywords: Alzheimer’s disease, dysexecutive syndrome, memory, vascular cognitive impairment

DOI: 10.3233/JAD-171097

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 625-633, 2018

Authors: Kim, Mi-Young | Noh, Yoojin | Son, Sang Joon | Shin, Sooyoung | Paik, Hee-Young | Lee, Sukhyang | Jung, Yi-Sook

Article Type: Research Article

Abstract: Background: Ischemic heart disease (IHD) is associated with cognitive decline and may contribute to an increased risk of dementia. Objective: The goal of the present study was to investigate whether cilostazol use is associated with a lower risk of incident dementia in Asian patients with IHD, and whether these effects differed based on sex. Methods: This retrospective cohort study was performed using the Korean National Insurance Claim Data of the Health Insurance Review and Assessment Service; the duration of the study was from January 1, 2007 to December 31, 2015. The study group comprised 66,225 patients …with IHD, aged >65 years, who had received cilostazol. Age- and sex-matched IHD patients without cilostazol exposure were selected as the control group. The risk of dementia was compared between the cilostazol and control groups. Results: Compared to the control group, total cilostazol users had a marginally significant lower risk of incident dementia. After stratification by sex, the reducing effect of cilostazol on incident dementia was significant in female participants, but not in male participants. Female patients who had cilostazol for over 2 years showed a clinically meaningful preventive effect (HR, 0.85; 95% CI, 0.82–0.88). Conclusions: This study suggested that cilostazol treatment may reduce the risk of incident dementia in Korean patients with IHD. Its beneficial effect was remarkably significant in female patients who received cilostazol for over a 2-year period. Show more

Keywords: Cilostazol, dementia, ischemic heart disease, sex difference

DOI: 10.3233/JAD-170895

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 635-644, 2018

Authors: Henley, Brandon C. | Shokouhi, Mahsa | Mahajan, Anushree Y. | Inan, Omer T. | Hajjar, Ihab

Article Type: Research Article

Abstract: Mental stress has been linked to various chronic diseases including Alzheimer’s disease, but the mechanisms underlying cognitive decline with mental stress are unknown. Reduced cardiovascular response to stress is associated with cardiovascular disease, and the latter is associated with cognitive impairment. We measured electrodermal activity, blood pressure, and cardiac hemodynamics in cognitively normal and mild cognitive impairment (MCI) adults (n  = 76, mean age = 58 years, 46% MCI) during rest, a math test, and face-name recall tasks to derive the following cardiovascular indicators: mean arterial pressure, heart rate, stroke volume and cardiac output. These indicators were compared between the two groups. Cerebral …blood perfusion via arterial spin-labeling MRI was measured in a subgroup who underwent an MRI scan (n  = 30). Following exposure to mental stress, a decrease in stroke volume (p  = 0.024) and cardiac output (p  = 0.005) was found in the MCI group, but an increase in both parameters in the cognitively normal group. This difference was largest during face-name recall (standardized difference in stroke volume = –0.50, p  = 0.029, and in cardiac output = –0.52, p  = 0.023). Cardiac output during mental stress, but not at rest, decreased with cerebral perfusion (normal: p  = 0.078, β = 1.97, R2  = 0.090; MCI: p  = 0.007, β = 2.02, R2  = 0.008). No significant difference was found between the two groups at rest. This preliminary study suggests that individuals with MCI have an insufficient cardiac output, and in turn lower cerebral perfusion in response to mental stress. Show more

Keywords: Cardiovascular reactivity, cerebral blood flow, cognitive impairment, functional magnetic resonance imaging, hemodynamics, mental health, stress, vascular disease

DOI: 10.3233/JAD-180036

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 645-654, 2018