Journal of Alzheimer's Disease - Volume 51, issue 4

Authors: Xu, Lele | Wu, Xia | Li, Rui | Chen, Kewei | Long, Zhiying | Zhang, Jiacai | Guo, Xiaojuan | Yao, Li | the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: For patients with mild cognitive impairment (MCI), the likelihood of progression to probable Alzheimer’s disease (AD) is important not only for individual patient care, but also for the identification of participants in clinical trial, so as to provide early interventions. Biomarkers based on various neuroimaging modalities could offer complementary information regarding different aspects of disease progression. The current study adopted a weighted multi-modality sparse representation-based classification method to combine data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, from three imaging modalities: Volumetric magnetic resonance imaging (MRI), fluorodeoxyglucose (FDG) positron emission tomography (PET), and florbetapir PET. We included 117 normal …controls (NC) and 110 MCI patients, 27 of whom progressed to AD within 36 months (pMCI), while the remaining 83 remained stable (sMCI) over the same time period. Modality-specific biomarkers were identified to distinguish MCI from NC and to predict pMCI among MCI. These included the hippocampus, amygdala, middle temporal and inferior temporal regions for MRI, the posterior cingulum, precentral, and postcentral regions for FDG-PET, and the hippocampus, amygdala, and putamen for florbetapir PET. Results indicated that FDG-PET may be a more effective modality in discriminating MCI from NC and in predicting pMCI than florbetapir PET and MRI. Combining modality-specific sensitive biomarkers from the three modalities boosted the discrimination accuracy of MCI from NC (76.7%) and the prediction accuracy of pMCI (82.5%) when compared with the best single-modality results (73.6% for MCI and 75.6% for pMCI with FDG-PET). Show more

Keywords: Florbetapir positron emission tomography, fluorodeoxyglucose positron emission tomography, magnetic resonance imaging, mild cognitive impairment, multi-modality, prediction, progressive mild cognitive impairment

DOI: 10.3233/JAD-151010

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1045-1056, 2016

Authors: Kim, Yoonhee | Kim, Chaeyoung | Jang, Hye Young | Mook-Jung, Inhee

Article Type: Research Article

Abstract: Amyloid-β (Aβ) is one of major molecules contributing to the pathogenesis of Alzheimer’s disease (AD). Aβ is derived from amyloid-β protein precursor (AβPP) through sequential cleavages by β- and γ -secretases. Regulation of these components is thought to be an important factor in Aβ generation during the pathogenesis of AD. AβPP, β-secretase, and γ -secretase reside in lipid rafts, where cholesterol regulates the integrity and flexibility of membrane proteins and Aβ is generated. However, the relationship between cholesterol and Aβ generation is controversial. In this study, we aimed to elucidate the direct effects of cholesterol depletion on AβPP processing using …AY9944, which blocks the last step of cholesterol biosynthesis and thus minimizes the unknown side effects of upstream inhibitors, such as HMG-CoA reductase inhibitors. Treatment with AY9944 decreased γ -secretase activity and Aβ generation. These results suggested that changes in membrane composition by lowering cholesterol with AY9944 affected γ -secretase activity and Aβ generation, which is associated with AD pathogenesis. Show more

Keywords: Alzheimer’s disease, amyloid-β, AY9944, cholesterol, γ-secretase

DOI: 10.3233/JAD-150982

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1057-1068, 2016

Authors: Bousiges, Olivier | Cretin, Benjamin | Lavaux, Thomas | Philippi, Nathalie | Jung, Barbara | Hezard, Sylvie | Heitz, Camille | Demuynck, Catherine | Gabel, Aurelia | Martin-Hunyadi, Catherine | Blanc, Frédéric

Article Type: Research Article

Abstract: Background: Dementia with Lewy bodies (DLB) symptoms are close to those of Alzheimer’s disease (AD), and the differential diagnosis is difficult especially early in the disease. Unfortunately, AD biomarkers in cerebrospinal fluid (CSF), and more particularly Aβ1 - 42 , appear to be altered in dementia with Lewy bodies (DLB). However, the level of these biomarkers has never been studied in the prodromal stage of the disease. Objective: To compare these biomarkers between DLB and AD, with a particular focus on the prodromal stage. Methods: A total of 166 CSF samples were collected at the memory clinic of …Strasbourg. They were obtained from prodromal DLB (pro-DLB), DLB dementia, prodromal AD (pro-AD), and AD dementia patients, and elderly controls. Phospho-Tau181 , total-Tau, Aβ42 , and Aβ40 were measured in the CSF. Results: At the prodromal stage, contrary to AD patients, DLB patients’ biomarker levels in the CSF were not altered. At the demented stage of DLB, Aβ42 levels were reduced as well as Aβ40 levels. Thus, the Aβ42 /Aβ40 ratio remained unchanged between the prodromal and demented stages, contrary to what was observed in AD. Tau and Phospho-Tau181 levels were unaltered in DLB patients. Conclusions: We have shown that at the prodromal stage the DLB patients had no pathological profile. Consequently, CSF AD biomarkers are extremely useful for differentiating AD from DLB patients particularly at this stage when the clinical diagnosis is difficult. Thus, these results open up new perspectives on the interpretation of AD biomarkers in DLB. Show more

Keywords: Aβ42, Aβ40, Aβ42/Aβ40 ratio, Alzheimer’s disease, cerebrospinal fluid biomarkers, dementia with Lewy bodies, dementia, phospho-Tau181, prodromal, total-Tau

DOI: 10.3233/JAD-150731

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1069-1083, 2016

Authors: Gomar, Jesus J. | Conejero-Goldberg, Concepcion | Davies, Peter | Goldberg, Terry E. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The earliest stage of preclinical Alzheimer’s disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42 ). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood. Objective: To examine dynamic interrelationships between Aβ42 and tau in preclinical AD. Methods: We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n … = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n  = 14); and 3) Aβ42 levels consistently abnormal (n  = 18). Results: In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p  = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = –0.60; p  = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42 ) predicted p-tau slope (increasing p-tau) (R2  = 0.47, p  = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p  <  0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau. Conclusions: The evolution of Aβ42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD. Show more

Keywords: Aβ42, brain atrophy, cerebrospinal fluid, cognition, p-tau, preclinical AD

DOI: 10.3233/JAD-150937

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1085-1097, 2016

Authors: Stern, Robert A. | Tripodis, Yorghos | Baugh, Christine M. | Fritts, Nathan G. | Martin, Brett M. | Chaisson, Christine | Cantu, Robert C. | Joyce, James A. | Shah, Sahil | Ikezu, Tsuneya | Zhang, Jing | Gercel-Taylor, Cicek | Taylor, Douglas D.

Article Type: Research Article

Abstract: Background: Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer’s disease, there is a need for methods to diagnose CTE during life through objective biomarkers. Objective: The aim of this study was to examine tau-positive …exosomes in plasma as a potential CTE biomarker. Methods: Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau. Results: The NFL group had higher exosomal tau than the control group (p  <  0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p  = 0.0126) and psychomotor speed (p  = 0.0093). Conclusion: These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker. Show more

Keywords: Biomarker, chronic traumatic encephalopathy, diagnosis, exosome, football, neurodegeneration, plasma, tau

DOI: 10.3233/JAD-151028

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1099-1109, 2016

Authors: Chai, Yuek Ling | Yeo, Hazel Kai-Hui | Wang, Jiehao | Hilal, Saima | Ikram, Mohammad Kamran | Venketasubramanian, Narayanaswamy | Wong, Boon-Seng | Chen, Christopher Li-Hsian

Article Type: Research Article

Abstract: Background and Objective: While the association for apolipoprotein ɛ4 allele (APOE4) with Alzheimer’s disease (AD) has been consistently confirmed, the association with vascular cognitive impairment (VCI) is unclear. We therefore explored the relationship of APOE with both AD and cerebrovascular disease (CeVD) by examining the prevalence of APOE4 in AD, AD with CeVD and vascular dementia (VaD), as well as in cognitive impairment no dementia (CIND) with and without CeVD. Methods: We performed a case-control study with subjects recruited from memory clinics and the community. All subjects underwent standardized brain neuroimaging, clinical and neuropsychological assessments, following which they …were classified using research criteria. Results: A total of 411 subjects; 92 controls with no cognitive impairment (NCI), 77 CIND without CeVD, 87 CIND with CeVD, 55 AD without CeVD, 68 AD with CeVD, and 32 VaD patients were recruited. Compared to NCI (16.3%), the prevalence of APOE4 carriers was significantly higher only in CIND (37.7%) and AD in the absence of CeVD (45.5%), but not in the three subgroups of VCI, namely CIND with CeVD (20.7%), AD with CeVD (27.9%) and VaD (25.0%). Logistic regression analyses also showed that APOE4 carriers were more likely to have CIND without CeVD (Odds Ratio [OR]: 3.34; 95% Confidence Interval [CI]: 1.59–7.03) and AD without CeVD (OR: 7.21; 95% CI: 2.74–18.98), but no such association was observed in the VCI subgroups. Conclusion: APOE4 is significantly associated with dementia and CIND due to AD pathology, but not with VCI. Show more

Keywords: Alzheimer’s disease, apolipoprotein ɛ4, cerebrovascular disease, cognitive impairment no dementia, vascular cognitive impairment, vascular dementia

DOI: 10.3233/JAD-150902

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1111-1118, 2016

Authors: Migliaccio, Raffaella | Gallea, Cécile | Kas, Aurélie | Perlbarg, Vincent | Samri, Dalila | Trotta, Laura | Michon, Agnès | Lacomblez, Lucette | Dubois, Bruno | Lehericy, Stéphane | Bartolomeo, Paolo

Article Type: Research Article

Abstract: Background: Posterior cortical atrophy (PCA) induces progressive dysfunction of ventral and dorsal visual networks. Little is known, however, about corresponding changes in functional connectivity (FC). Objectives: To investigate FC changes in the visual networks, their relationship with cortical atrophy, and the association with Alzheimer’s disease (AD) pathology. Methods: Ten PCA patients and 28 age-matched controls participated in the study. Using resting state fMRI, we measured FC in ventral and dorsal cortical visual networks, defined on the basis of a priori knowledge of long-range white matter connections. To assess the relationships with AD, we determined AD …biomarkers in cerebrospinal fluid and FC in the default mode network (DMN), which is vulnerable to AD pathology. Voxel-based morphometry analysis assessed the pattern of grey matter (GM) atrophy. Results: PCA patients showed GM atrophy in bilateral occipital and inferior parietal regions. PCA patients had lower FC levels in a ventral network than controls, but higher FC in inferior components of the dorsal network. In particular, the increased connectivity correlated with greater GM atrophy in occipital regions. All PCA patients had positive cerebrospinal fluid biomarkers for AD; however, FC in global DMN did not differ from controls. Conclusions: FC in PCA reflects brain structure in a non-univocal way. Hyperconnectivity of dorsal networks may indicate aberrant communication in response to posterior brain atrophy or processes of neural resilience during the initial stage of brain dysfunction. The lack of difference from controls in global DMN FC highlights the atypical nature of PCA with respect to typical AD. Show more

Keywords: Brain resilience, dorsal stream, functional connectivity, posterior cortical atrophy, ventral stream

DOI: 10.3233/JAD-150934

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1119-1130, 2016

Authors: Pasquier, Florence | Sadowsky, Carl | Holstein, Ann | Leterme, Ghislaine Le Prince | Peng, Yahong | Jackson, Nicholas | Fox, Nick C. | Ketter, Nzeera | Liu, Enchi | Ryan, J. Michael | for the ACC-001 (QS-21) Study Team

Article Type: Research Article

Abstract: Vanutide cridificar (ACC-001), an immunotherapeutic vaccine, is a potentially disease-modifying therapy that aims to reduce brain amyloid-β (Aβ) plaques in patients with Alzheimer’s disease (AD). ACC-001 was evaluated in two phase 2a, multicenter, randomized, third party–unblinded, placebo-controlled, multiple ascending–dose studies of ACC-001 (3μg, 10μg, 30μg) with and without QS-21 adjuvant that enrolled patients with mild-to-moderate AD (n  = 245). Patients were treated with up to five doses of study vaccine or placebo and followed for safety and tolerability (primary objective) and anti-Aβ IgG immunogenicity (secondary objective) up to 12 months after the last vaccination. Exploratory assessments included cognitive/functional measures, brain magnetic …resonance imaging (MRI) volumetry, and pharmacodynamic markers in plasma and cerebrospinal fluid (CSF). The most frequent treatment-emergent adverse events (≥10%) were local injection reactions and headache. Amyloid-related imaging abnormalities with vasogenic edema occurred in two (0.8%) patients (ACC-001 30μg + QS-21; ACC-001 10μg). ACC-001 + QS-21 elicited consistently higher peak and sustained anti-Aβ IgG titers compared with ACC-001 alone. Plasma Aβx–40 was significantly higher in all ACC-001 + QS-21 groups versus placebo (weeks 16–56), with no evidence of dose response. Exploratory cognitive evaluations, volumetric brain MRI, and CSF biomarkers did not show differences or trends between treatment groups and placebo. ACC-001 with or without QS-21 adjuvant has an acceptable safety profile in patients with mild-to-moderate AD. Show more

Keywords: Active immunization, Alzheimer’s disease, amyloid-β peptides, amyloid-β protein, amyloid plaques, clinical trial, immunotherapy

DOI: 10.3233/JAD-150376

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1131-1143, 2016

Authors: Rattanabannakit, Chatchawan | Risacher, Shannon L. | Gao, Sujuan | Lane, Kathleen A. | Brown, Steven A. | McDonald, Brenna C. | Unverzagt, Frederick W. | Apostolova, Liana G. | Saykin, Andrew J. | Farlow, Martin R.

Article Type: Research Article

Abstract: Background: The perception of cognitive decline by individuals and those who know them well (“informants”) has been inconsistently associated with objective cognitive performance, but strongly associated with depressive symptoms. Objective: We investigated associations of self-report, informant-report, and discrepancy between self- and informant-report of cognitive decline obtained from the Cognitive Change Index (CCI) with cognitive test performance and self-reported depressive symptoms. Methods: 267 participants with normal cognition, mild cognitive impairment (MCI), or mild dementia were included from a cohort study and memory clinic. Association of test performance and self-rated depression (Geriatric Depression Scale, GDS) with CCI scores …obtained from subjects (CCI-S), their informants (CCI-I), and discrepancy scores between subjects and informants (CCI-D; CCI-S minus CCI-I) were analyzed using correlation and analysis of covariance (ANCOVA) models. Results: CCI-S and CCI-I scores showed high internal consistency (Cronbach alpha 0.96 and 0.98, respectively). Higher scores on CCI-S and CCI-I, and lower scores on the CCI-D, were associated with lower performance on various cognitive tests in both univariate and in ANCOVA models adjusted for age, gender, and education. Adjustment for GDS slightly weakened the relationships between CCI and test performance but most remained significant. Conclusion: Self- and informant-report of cognitive decline, as measured by the CCI, show moderately strong relationships with objective test performance independent of age, gender, education, and depressive symptoms. The CCI appears to be a valid cross-sectional measure of self and informant perception of cognitive decline across the continuum of functioning. Studies are needed to address the relationship of CCI scores to longitudinal outcome. Show more

Keywords: Alzheimer’s disease, cognitive change index, cognitive performance, subjective cognitive decline, validation

DOI: 10.3233/JAD-150729

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1145-1155, 2016

Authors: Guillot, Florence | Kemppainen, Susanna | Levasseur, Gregoire | Miettinen, Pasi O. | Laroche, Serge | Tanila, Heikki | Davis, Sabrina

Article Type: Research Article

Abstract: Although it is well established that insulin/IGF and BDNF signaling are dysfunctionally regulated in Alzheimer’s disease, there are very few studies documenting changes in major target proteins in different murine models of the disease. We investigated a panel of proteins in the PI3K-Akt and MAPK/ERK cascades in parietal cortex, dentate gyrus and CA1 in 13-month-old AβPP/PS1 transgenic mice to determine whether amyloid pathology is associated with basal dysregulation of these proteins or following exposure to novelty. The most striking effect we found was that there was little common regulation of proteins either by pathology alone or exposure to novelty across …the three structures, suggesting dysfunctional mechanisms that occur simultaneously have important structure specificity. CA1 shared certain dysfunctional regulation of proteins in the MAPK/ERK cascade, but shared dysfunctional regulation of the PI3K/Akt cascade with the dentate gyrus. Changes in ERK/CREB in transgenic mice did not result in coordinated dysfunction of the downstream transcription factor, Egr1, as it was overexpressed in a normal manner following exposure to novelty. In the PI3K-Akt cascade, there was a flagrant increase in the levels of proteins associated with inflammation, such as NFκB, and structure specific regulation of proteins associated with autophagy, such as mTOR and FOXO1 and lack of regulation of Beclin-1. Finally, Beclin-1 was increased by novelty in wild-type mice but deficient in transgenic mice. Results are interpreted in terms of structure-specific dysfunctional regulation of signaling mechanisms associated with Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, autophagy, Beclin 1, CA1, cortex, dentate gyrus, inflammation, mTOR, NFκB, transgenic mice

DOI: 10.3233/JAD-150926

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1157-1173, 2016