Journal of Alzheimer's Disease - Volume 45, issue 1

Authors: Huang, Yunpeng | Wu, Zhihao | Zhou, Bing

Article Type: Research Article

Abstract: Tau hyperphosphorylation has been found in several neurodegenerative diseases such as Alzheimer's disease (AD), Down syndrome, and amyotrophic lateral sclerosis (ALS). However, factors affecting tau hyperphosphorylation are not yet clearly understood. SOD1, a Cu/Zn superoxide dismutase whose mutations can cause adult-onset ALS, is believed to be involved in the pathology of Down syndrome. In this work, the model organism Drosophila was used to study the possible link between hSOD1 and tau. Our results show that hSOD1, and to a higher degree hSOD1(A4V), can increase tau toxicity in Drosophila and exacerbate the corresponding neurodegeneration phenotype. The increased tau toxicity appears to …be explainable by elevated tau phosphorylation. Tau(S2A), a tau mutant with impaired phosphorylation capabilities, does not respond to expression of hSOD1 and hSOD1(A4V). We suggest that increased SOD1 expression can lead to tau hyperphosphorylation, which might serve as an important contributing factor to the etiology of Down syndrome and SOD1-related ALS disease. Show more

Keywords: Drosophila, hSOD1, hyperphosphorylation, tau

DOI: 10.3233/JAD-141608

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 235-244, 2015

Authors: Qin, Wei | Jia, Xiangfei | Wang, Fen | Zuo, Xiumei | Wu, Liyong | Zhou, Aihong | Li, Dan | Min, Baoquan | Wei, Cuibai | Tang, Yi | Xing, Yi | Dong, Xiumin | Wang, Qi | Gao, Yining | Li, Ying | Jia, Jianping

Article Type: Research Article

Abstract: Evidence has shown that aberrant angiogenesis is an integral part of Alzheimer's disease (AD). Angiogenesis is a complex process requiring successive activation of a rather large series of factors. The aim of this study was to determine which angiogenesis molecule(s) abnormalities were changed in plasma of AD subjects and whether plasma levels of angiogenesis factors were associated with cognitive function and risk of AD. Discovery-phase antibody arrays were used to detect plasma concentrations of 55 angiogenesis-related factors. Enzyme-linked immunosorbent assays (ELISAs) in a large cohort were further performed to identify the association of plasma angiogenesis factors with AD. We found …that plasma angiogenin (ANG) and tissue inhibitor of matrix metalloproteinase-4 (TIMP-4) levels were higher in patients with AD than those in normal subjects. Significantly higher ANG and TIMP-4 were observed in the severe AD group relative to the mild AD. There were different levels of plasma ANG and TIMP-4 compared with vascular dementia and other dementias. Age or gender had no major effects on levels of these proteins. Plasma ANG and TIMP-4 levels tended to be higher in ApoE ε4 carriers compared with non-carriers, but not significantly. A multiple regression analysis after adjusting for covariates revealed correlations between plasma ANG and TIMP-4 and the MMSE and CDR. Higher plasma ANG and TIMP-4 levels were associated with significant AD risk. These results demonstrate that plasma ANG and TIMP-4 may reflect the severity of cognitive function impairment, and higher levels were associated with risk of AD. Show more

Keywords: Alzheimer's disease, angiogenin, plasma, risk, TIMP-4

DOI: 10.3233/JAD-142409

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 245-252, 2015

Authors: Susanto, Thomas Adi Kurnia | Pua, Emmanuel Peng Kiat | Zhou, Juan | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Knowledge of Alzheimer’s disease (AD) manifestation in the pre-dementia stage facilitates the selection of appropriate measures for early detection and disease progression. Objective: To examine the trajectories of cognitive performance, gray matter volume (GMV), and cerebrospinal fluid (CSF) biomarkers, together with the influence of apolipoprotein E (APOE) in subjects with amyloid-β (Aβ) deposits across the pre-clinical to dementia stages of AD. Methods: 356 subjects were dichotomized into Aβ+ and Aβ− groups based on their CSF Aβ1-42 level. We derived AD-related atrophic regions (AD-ROIs) using the voxel-based morphometry approach. We characterized the trajectories of cognitive …scores, GMV at AD-ROIs, and CSF biomarkers from preclinical to disease stages in Aβ+ subjects. The effect of APOE ε4 genotype on these trajectories was examined. Results: Impairments in executive functioning/processing speed (EF/PS) and atrophy at the right supramarginal/inferior parietal gyrus were detected in cognitively normal Aβ+ subjects. Together with the APOE ε4 carrier status, these measures showed potential to identify cognitively normal elderly with abnormal CSF Aβ1-42 level in another independent cohort. Subsequently, impairment in memory, visuospatial, language, and attention as well as atrophy in the temporal lobe, thalamus, and mid-cingulate cortex were detectable in Aβ+ mild cognitive impairment (MCI) subjects. In MCI and dementia Aβ+ subjects, ε4 carriers had more severe atrophy of the medial temporal lobe and memory impairment but higher EF/PS compared to non-carriers. Conclusions: EF/PS decline and right parietal atrophy might act as non-invasive screening tests for abnormal amyloid deposition in cognitively normal elderly. APOE modulation on subsequent trajectories in cognition and atrophy should be taken into account when analyzing disease progression. Show more

Keywords: Alzheimer's disease, amyloid-β deposition, APOE genotype, magnetic resonance imaging, mild cognitive impairment, preclinical

DOI: 10.3233/JAD-142451

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 253-268, 2015

Authors: Sun, Yingni | Rong, Xianfang | Lu, Wenwen | Peng, Ying | Li, Jiang | Xu, Shaofeng | Wang, Ling | Wang, Xiaoliang

Article Type: Research Article

Abstract: The aim of this study was to investigate potential biomarkers of Alzheimer's disease (AD). Changes in protein expression in brain tissues from AβPP/PS1 transgenic mice were evaluated using two-dimensional gel electrophoresis combined with LC-MS/MS. A total of 23 differentially expressed proteins were successfully identified in brain tissues of which 11 were validated by western blot. Then, the levels of these differentially expressed proteins in serum from AD patients and healthy controls were examined. Of these 11 proteins, levels of 5 changed in the same direction in the serum of AD patients as they did in mouse brain: cathepsin B, VDAC1, …and cofilin-2 increased, and Alix and ACAP1 decreased. Alix, cofilin-2, and ACAP1 have not been previously associated with AD. More importantly, the serum levels of Alix, cofilin-2, and ACAP1 were significantly different between AD patients and healthy controls. Furthermore, the expressions of cathepsin B, cofilin-2, VDAC1, and ACAP1 strongly correlated with the Mini-Mental State Examination scores of the AD patients. The results indicate that these proteins are putative biomarkers of AD which may be useful in its diagnosis and in the evaluation of new anti-AD drugs both in pre-clinical and clinical studies. Show more

Keywords: Alzheimer's disease, biomarker, diagnosis, neurodegeneration, proteomics, serum, transgenic mice

DOI: 10.3233/JAD-142805

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 269-282, 2015

Authors: Shinagawa, Shunichiro | Nakajima, Shinichiro | Plitman, Eric | Graff-Guerrero, Ariel | Mimura, Masaru | Nakayama, Kazuhiko | Miller, Bruce L.

Article Type: Research Article

Abstract: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by changes in behavior and language caused by focal degeneration of the frontal and anterior temporal lobes. The behavioral symptoms are distressing to patients and their caregivers. Non-pharmacological management is important as no disease-specific pharmacological treatment for FTD is currently available. The primary objective is to review the literature on non-pharmacological management for FTD and to propose directions for future research, with reference to findings. A search was performed using PubMed, MEDLINE, and EMBASE. Search terms included “frontotemporal dementia”, and words related to non-pharmacological management, and it identified a total of 858 …articles. Results revealed that very few randomized controlled trials exist on non-pharmacological management interventions for FTD. These interventions have been proposed by literature based on clinical experience. A small number of studies have supported behavioral management techniques that exploit disease-specific behaviors and preserved functions in patients with FTD, along with the management of caregivers' distress. These limitations warrant well-designed large-scale research to examine effects of non-pharmacological interventions on behavioral symptoms of FTD. Show more

Keywords: Behavioral management, caregiver support, environmental strategies, non-pharmacological interventions in frontotemporal dementia

DOI: 10.3233/JAD-142109

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 283-293, 2015

Authors: Muñiz, Ruben | Serra, Cristina Massegú | Reisberg, Barry | Rojo, José Manuel | del Ser, Teodoro | Peña Casanova, Jordi | Olazarán, Javier

Article Type: Research Article

Abstract: Background: Little is known about the long-term acceptance and effects of cognitive and motor stimulation interventions (CMSI) in Alzheimer’s disease (AD). Objective: To evaluate a replicable CMSI program for mild cognitive impairment (MCI) and mild-to-moderate AD persons. Methods: Eighty-four non-institutionalized subjects with AD were randomized to receive either CMSI, administered by a single care provider, or standard support. Cognition, activities of daily living (ADL), mood, and study partner’s subjective burden were assessed by blinded raters. Data on institutionalization, psychiatric medications, and demise were collected by the study physicians. Random effects model and survival analyses were conducted, …after 2 and 3 years of study. Results: Three-year assessments could be performed by the physician in 85% and by the blinded rater in 66% of subjects. Significant benefits were observed in basic ADL at the 2- and 3-year assessments, whereas instrumental ADL showed benefits only up to the second year of intervention (p < 0.05). Conclusion: Long-term cognitive-motor stimulation is well accepted and produces functional benefits in subjects with AD, with no extra subjective burden in the partner. Show more

Keywords: Alzheimer's disease, cognitive stimulation, cognitive-motor stimulation intervention, long-term effects, non-pharmacological therapies, randomized controlled trial

DOI: 10.3233/JAD-142364

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 295-304, 2015

Authors: Wilkins, Heather M. | Carl, Steven M. | Weber, Sam G. | Ramanujan, Suruchi A. | Festoff, Barry W. | Linseman, Daniel A. | Swerdlow, Russell H.

Article Type: Research Article

Abstract: Neuroinflammation occurs in Alzheimer's disease (AD). While AD genetic studies implicate inflammation-relevant genes and fibrillar amyloid-β protein promotes inflammation, our understanding of AD neuroinflammation nevertheless remains incomplete. In this study we hypothesized damage-associated molecular pattern (DAMP) molecules arising from mitochondria, intracellular organelles that resemble bacteria, could contribute to AD neuroinflammation. To preliminarily test this possibility, we exposed neuronal and microglial cell lines to enriched mitochondrial lysates. BV2 microglial cells treated with mitochondrial lysates showed decreased TREM2 mRNA, increased TNFα mRNA, increased MMP-8 mRNA, increased IL-8 mRNA, redistribution of NFκB to the nucleus, and increased p38 MAPK phosphorylation. SH-SY5Y neuronal cells …treated with mitochondrial lysates showed increased TNFα mRNA, increased NFκB protein, decreased IκBα protein, increased AβPP mRNA, and increased AβPP protein. Enriched mitochondrial lysates from SH-SY5Y cells lacking detectable mitochondrial DNA (ρ0 cells) failed to induce any of these changes, while mtDNA obtained directly from mitochondria (but not PCR-amplified mtDNA) increased BV2 cell TNFα mRNA. These results indicate at least one mitochondrial-derived DAMP molecule, mtDNA, can induce inflammatory changes in microglial and neuronal cell lines. Our data are consistent with the hypothesis that a mitochondrial-derived DAMP molecule or molecules could contribute to AD neuroinflammation. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, inflammation, mitochondria, mtDNA, TREM2

DOI: 10.3233/JAD-142334

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 305-318, 2015

Article Type: Correction

DOI: 10.3233/JAD-159001

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 319-319, 2015

Article Type: Other

DOI: 10.3233/JAD-142335

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 321-324, 2015