Journal of Alzheimer's Disease - Volume 55, issue 2

Authors: Kepp, Kasper Planeta

Article Type: Research Article

Abstract: The inability to effectively halt or cure Alzheimer’s disease (AD), exacerbated by the recent failures of high-profile clinical trials, emphasizes the urgent need to understand the complex biochemistry of this major neurodegenerative disease. In this paper, ten central, current challenges of the major paradigm in the field, the amyloid hypothesis, are sharply formulated. These challenges together show that new approaches are necessary that address data heterogeneity, increase focus on the proteome level, use available human patient data more actively, account for the aging phenotype as a background model of the disease, unify our understanding of the interplay between genetic and …non-genetic risk factors, and combine into one framework both the familial and sporadic forms of the disease. Show more

Keywords: Aging, Alzheimer’s disease, amyloid hypothesis, challenges, toxicity

DOI: 10.3233/JAD-160550

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 447-457, 2017

Authors: Duclos, Harmony | de La Sayette, Vincent | Bonnet, Anne-Laure | Viard, Armelle | Eustache, Francis | Desgranges, Béatrice | Laisney, Mickaël

Article Type: Short Communication

Abstract: Although frontal presentations of Alzheimer’s disease (fv-AD) have already been described in the literature, we still know little about patients’ social cognitive abilities, especially their theory of mind (ToM). We report the case of FT, a 61-year-old woman who was diagnosed with fv-AD. Two assessments of social cognition, using a false-belief task, the Reading the Mind in the Eyes test, and a task probing knowledge of social norms, were performed one year apart. FT exhibited cognitive ToM and social knowledge deficits from the onset. Affective ToM was initially preserved, but deteriorated as the disease progressed.

Keywords: Alzheimer’s disease, behavioral symptoms, social norms, theory of mind

DOI: 10.3233/JAD-160690

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 459-463, 2017

Authors: Dronse, Julian | Fliessbach, Klaus | Bischof, Gérard N. | von Reutern, Boris | Faber, Jennifer | Hammes, Jochen | Kuhnert, Georg | Neumaier, Bernd | Onur, Oezguer A. | Kukolja, Juraj | van Eimeren, Thilo | Jessen, Frank | Fink, Gereon R. | Klockgether, Thomas | Drzezga, Alexander

Article Type: Short Communication

Abstract: The clinical heterogeneity of Alzheimer’s disease is not reflected in the rather diffuse cortical deposition of amyloid-β. We assessed the relationship between clinical symptoms, in vivo tau pathology, amyloid distribution, and hypometabolism in variants of Alzheimer’s disease using novel multimodal PET imaging techniques. Tau pathology was primarily observed in brain regions related to clinical symptoms and overlapped with areas of hypometabolism. In contrast, amyloid-β deposition was diffusely distributed over the entire cortex. Tau PET imaging may thus serve as a valuable biomarker for the localization of neuronal injury in vivo and may help to validate atypical subtypes of …Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid, 18F-AV-1451, 18F-FDG, molecular imaging, multimodal imaging, Pittsburghcompound B, positron-emission tomography, T-807, tau protein

DOI: 10.3233/JAD-160316

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 465-471, 2017

Authors: Darst, Burcu F. | Koscik, Rebecca L. | Racine, Annie M. | Oh, Jennifer M. | Krause, Rachel A. | Carlsson, Cynthia M. | Zetterberg, Henrik | Blennow, Kaj | Christian, Bradley T. | Bendlin, Barbara B. | Okonkwo, Ozioma C. | Hogan, Kirk J. | Hermann, Bruce P. | Sager, Mark A. | Asthana, Sanjay | Johnson, Sterling C. | Engelman, Corinne D.

Article Type: Research Article

Abstract: Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer’s disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer’s Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer’s Project’s meta-analysis, we identified clusters of genes that grouped into pathways involved in amyloid-β (Aβ) deposition and neurodegeneration: Aβ …clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aβ deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging in 168 individuals, and cerebrospinal fluid Aβ deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE , suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD. Show more

Keywords: Alzheimer’s disease, amyloid-beta, APOE, cerebrospinal fluid, cognitive function, genetic risk scores, genetics, Pittsburgh compound B, polygenic risk scores, WRAP

DOI: 10.3233/JAD-160195

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 473-484, 2017

Authors: Kim, Younggwang | Lee, Dongkyun | Cho, Kyoo Ho | Lee, Jae Jung | Ham, Jee Hyun | Ye, Byoung Seok | Lee, Seung-Koo | Lee, Jong-Min | Sohn, Young H. | Lee, Phil Hyu

Article Type: Research Article

Abstract: Background: Aging is the most important risk factor of development of dementia in Parkinson’s disease (PD), but there are no data on clinical and radiological heterogeneity of PD dementia (PDD) depending on age at onset. Objectives: The goal of this study was to examine whether patients with PDD are clinically and radiologically heterogeneous depending on age at onset. Methods: A total of 116 patients with PD dementia and 121 age- and sex-matched normal controls were enrolled. The subjects were divided into early-onset (EOPDD; n  = 39) and late-onset (LOPDD; n  = 77) PDD with the respective age-matched …control group based on a cutoff value of 70 years. The effects of diagnosis, age, and their interaction on neuropsychological tests, cortical thickness, and substantia innominata volume were assessed using analysis of covariance. Results: EOPDD patients had a poorer cognitive performance on digit backward, forward span test (p  = 0.011 and 0.05), and visual recognition memory function (p  = 0.012) compared with LOPDD patients. Additionally, EOPDD patients exhibited cortical thinning in the left anterior cingulate gyrus and the right inferior temporal gyrus, with significantly decreased normalized substantia innominata volume (p  = 0.044). Conclusions: Our data demonstrated that EOPDD patients exhibit poorer cognitive performance and more severe atrophy in the cortex and substantia innominata, implying that EOPDD may be a distinct phenotype different from LOPDD. Show more

Keywords: Age at onset, neuroanatomical correlates, neurocognitive performance, Parkinson’s disease dementia

DOI: 10.3233/JAD-160597

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 485-495, 2017

Authors: Zhang, Yan-Ping | Miao, Rujuan | Li, Qing | Wu, Tianfeng | Ma, Fei

Article Type: Research Article

Abstract: Docosahexaenoic acid (DHA) is important for brain function, and higher DHA intake is inversely correlated with relative risk of Alzheimer’s disease. The potential benefits of DHA supplementation in people with mild cognitive impairment (MCI) have not been fully examined. Our study aimed to determine the effect of DHA supplementation on cognitive function and hippocampal atrophy in elderly subjects with MCI. This was a randomized, double-blind, placebo-controlled trial in Tianjin, China. 240 individuals with MCI aged 65 years and over were recruited and equalized randomly allocated to the DHA or the placebo group. Participants received 12-month DHA supplementation (2 g/day) or corn …oil as placebo. Both global and specific subdomains of cognitive function and hippocampal volume were measured at baseline, 6 months, and 12 months. Both changes were analyzed by repeated-measure analysis of variance (ANOVA). This trial has been registered: ChiCTR-IOR-15006058. A total of 219 participants (DHA: 110, Placebo: 109) completed the trial. The change in mean serum DHA levels was greater in the intervention group (+3.85%) compared to the control group (+1.06%). Repeated-measures analyses of covariance showed that, over 12 months, there was a significant difference in the Full-Scale Intelligence Quotient (η p 2  = 0.084; p  = 0.039), Information (η p 2  = 0.439; p  = 0.000), and Digit Span (η p 2  = 0.375; p  = 0.000) between DHA-treated versus the placebo group. In addition, there were significant differences in volumes of left hippocampus (η p 2  = 0.121, p  = 0.016), right hippocampus (η p 2  = 0.757, p  = 0.008), total hippocampus (η p 2  = 0.124, p  = 0.023), and global cerebrum (η p 2  = 0.145, p  = 0.032) between the two groups. These findings suggest that DHA supplementation (2 g/day) for 12 months in MCI subjects can significantly improve cognitive function and slow the progression of hippocampal atrophy. Larger, longer-term confirmatory studies are warranted. Show more

Keywords: Alzheimer’s disease, cognitive function, docosahexaenoic acid, hippocampal volume, randomized controlled trial

DOI: 10.3233/JAD-160439

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 497-507, 2017

Authors: Xie, Bing | Liu, Zanchao | Jiang, Lei | Liu, Wei | Song, Mei | Zhang, Qingfu | Zhang, Rui | Cui, Dongsheng | Wang, Xueyi | Xu, Shunjiang

Article Type: Research Article

Abstract: Evidence suggests that individuals with amnestic mild cognitive impairment (aMCI) tend to progress to probable Alzheimer’s disease (AD) with aging. This study was performed to examine whether circulating miRNAs could be potential predictors for the progression of aMCI to AD. A total of 458 patients with aMCI were included in this study, and the clinical data were collected at two time points: the baseline and the follow-up assessment. These aMCI patients were classified into two groups after 5 years: aMCI-stable group (n  = 330) and AD-conversion group (n  = 128). The expression of miR-206 and miR-132 and the levels of BDNF and …SIRT1 in serum were detected using a quantitative real-time RT-PCR (qPCR) and the ELISA method, respectively. Kaplan-Meier method (Log-rank test) was used for univariate survival analysis. Cox proportional hazard model was used to estimate the prognostic value of miRNAs in conversion from aMCI to AD. At the baseline, serum levels of miR-206 in aMCI-AD group were significantly elevated compared to aMCI-aMCI group and the same trend was found at 5-year follow-up time point as well. There were no significant differences in serum levels of miR-132 between the conversion and non-conversion group at both time points. Kaplan-Meier analysis showed significant correlation between AD conversion and higher serum levels of miR-206 for aMCI patients (HR  = 3.60, 95% CI: 2.51– 5.36, p  < 0.001). Multivariate Cox regression analysis revealed that serum miR-206 and its target BDNF were significant independent predictors for AD conversion (HR  = 4.22, p  < 0.001). These results suggested that increased serum miR-206 level might be a potential predictor of conversion from aMCI to AD. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, circulating microRNA, follow-up study, predictor

DOI: 10.3233/JAD-160468

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 509-520, 2017

Authors: Hafkemeijer, Anne | Möller, Christiane | Dopper, Elise G.P. | Jiskoot, Lize C. | van den Berg-Huysmans, Annette A. | van Swieten, John C. | van der Flier, Wiesje M. | Vrenken, Hugo | Pijnenburg, Yolande A.L. | Barkhof, Frederik | Scheltens, Philip | van der Grond, Jeroen | Rombouts, Serge A.R.B.

Article Type: Research Article

Abstract: Background/Objective: Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. We applied longitudinal resting state functional magnetic resonance imaging (fMRI) to delineate functional brain connections relevant for disease progression and diagnostic accuracy. Methods: We used two-center resting state fMRI data of 20 AD patients (65.1±8.0 years), 12 bvFTD patients (64.7±5.4 years), and 22 control subjects (63.8±5.0 years) at baseline and 1.8-year follow-up. We used whole-network and voxel-based network-to-region analyses to study group differences in functional connectivity at baseline and follow-up, and longitudinal changes in connectivity within and between groups. …Results: At baseline, connectivity between paracingulate gyrus and executive control network, between cuneal cortex and medial visual network, and between paracingulate gyrus and salience network was higher in AD compared with controls. These differences were also present after 1.8 years. At follow-up, connectivity between angular gyrus and right frontoparietal network, and between paracingulate gyrus and default mode network was lower in bvFTD compared with controls, and lower compared with AD between anterior cingulate gyrus and executive control network, and between lateral occipital cortex and medial visual network. Over time, connectivity decreased in AD between precuneus and right frontoparietal network and in bvFTD between inferior frontal gyrus and left frontoparietal network. Longitudinal changes in connectivity between supramarginal gyrus and right frontoparietal network differ between both patient groups and controls. Conclusion: We found disease-specific brain regions with longitudinal connectivity changes. This suggests the potential of longitudinal resting state fMRI to delineate regions relevant for disease progression and for diagnostic accuracy, although no group differences in longitudinal changes in the direct comparison of AD and bvFTD were found. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, frontotemporal lobar degeneration, functional connectivity, longitudinal, resting state fMRI, resting state networks

DOI: 10.3233/JAD-150695

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 521-537, 2017

Authors: Miranda, Luís F.J.R. | Gomes, Karina B. | Tito, Pedro A.L. | Silveira, Josianne N. | Pianetti, Gerson A. | Byrro, Ricardo M.D. | Peles, Patrícia R.H. | Pereira, Fernando H. | Santos, Thiago R. | Assini, Arthur G. | Ribeiro, Valéria V. | Moraes, Edgar N. | Caramelli, Paulo

Article Type: Research Article

Abstract: The clinical response to donepezil in patients with mild and moderate dementia was investigated in relation to the drug plasma concentration and APOE and CYP2D6 polymorphisms. In a prospective naturalistic observational study, 42 patients with Alzheimer’s disease (AD) and AD with cerebrovascular disease who took donepezil (10 mg) for 12 months were evaluated. Their DNA was genotyped, and the donepezil plasma concentrations were measured after 3, 6, and 12 months. Good responders scored ≥–1 on the Mini-Mental State Examination at 12 months in comparison to the baseline score. The study results indicated the good response pattern was influenced by …the concentration of donepezil, but not by APOE and CYP2D6 polymorphisms. Show more

Keywords: Alzheimer’s disease, APOE, CYP2D6, donepezil, genetics, naturalistic study

DOI: 10.3233/JAD-160164

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 539-549, 2017

Authors: Huey, Edward D. | Lee, Seonjoo | Cheran, Gayathri | Grafman, Jordan | Devanand, Davangere P. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Apathy is a common and problematic symptom of several neurodegenerative illnesses, but its neuroanatomical bases are not understood. Objective: To determine the regions associated with apathy in subjects with mild Alzheimer’s disease (AD) using a method that accounts for the significant co-linearity of regional atrophy and neuropsychiatric symptoms. Methods: We identified 57 subjects with mild AD (CDR = 1) and neuropsychiatric symptoms in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. We performed a multivariate multiple regression with LASSO regularization on all symptom subscales of the Neuropsychiatric Inventory and the whole-brain ROI volumes calculated from their baseline …MRIs with FreeSurfer. We compared our results to those from a previous study using the same method in patients with frontotemporal dementia (FTD) and corticobasal syndrome (CBS). Results: Of neuropsychiatric symptoms, apathy showed the most robust neuroanatomical associations in the AD subjects. Atrophy of the following regions were independently associated with apathy: the ventromedial prefrontal cortex; ventrolateral prefrontal cortex; posterior cingulate cortex and adjacent lateral cortex; and the bank of the superior temporal sulcus. These results replicate previous studies using FTD and CBS patients, mostly agree with the previous literature on apathy in AD, and correspond to the Medial and Orbital Prefrontal Cortex networks identified in non-human primates. Conclusion: The current study, previous studies from our laboratory, and the previous literature suggest that impairment of the same brain networks involved in arousal, threat response, and reward processing are associated with apathy in AD and FTD. Show more

Keywords: Apathy, Alzheimer’s disease, frontotemporal dementia, magnetic resonance imaging, neuropsychiatry

DOI: 10.3233/JAD-160107

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 551-558, 2017