Journal of Alzheimer's Disease - Volume 56, issue 1

Authors: Jacob, Louis | Bohlken, Jens | Kostev, Karel

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a common mental disorder affecting around 16% of elderly people without dementia. MCI is considered an intermediate state between normal cognition and dementia. Objective: To analyze risk factors for the development of MCI in German primary care practices. Methods: In total, 3,604 MCI patients and 3,604 controls without MCI were included between January 2010 and December 2015. Several disorders potentially associated with MCI were determined. Multivariate logistic regression models were fitted with MCI as a dependent variable and other disorders as potential predictors. Results: The mean age …was 75.2 years and 45.3% of patients were men. MCI development was found to be associated with 12 disorders: intracranial injury, anxiety disorder, depression, mental and behavioral disorders due to alcohol use, stroke, hyperlipidemia, obesity, hypertension, Parkinson’s disease, sleep disorder, coronary heart disease, and diabetes with odds ratios ranging from 1.13 (diabetes) to 2.27 (intracranial injury). Conclusion: Intracranial injury, anxiety, and depression showed the strongest association with MCI. Further analyses are needed to gain a better understanding of the MCI risk factors. Show more

Keywords: Germany, mild cognitive impairment, primary practices, risk factors

DOI: 10.3233/JAD-160875

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 379-384, 2017

Authors: Shen, Liang | Liu, Lu | Ji, Hong-Fang

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative brain disease and is the most common form of dementia. In recent years, many studies indicated the association of gut microbiota changes with metabolic diseases. However, the gut microbiota of AD has not been investigated. The present study aims to compare the gut microbiota in APP/PS1 transgenic mice of AD and C57/Bl6 wild-type (WT) mice by pyrosequencing the V3 and V4 regions of the bacterial 16S ribosomal RNA genes. The 3-, 6-, and 8-month-old APP/PS1 and WT mice were used to explore the effects of age on the gut microbiota. First, the results indicated …that impaired spatial learning and memory appeared in 6-month-old APP/PS1 mice and was further aggravated in the 8-month-old group, which was consistent with immunohistochemical studies of amyloid plaque. Second, AD histological and behavioral manifestations in the APP/PS1 mice were found to be correlated with a specific gut microbiome state. Third, the microbiota diversity of APP/PS1 mice decreased with increased age. Fourth, further inspection showed that the abundance of Helicobacteraceae and Desulfovibrionaceae at the family level and Odoribacter and Helicobacter at the genus level increased significantly in APP/PS1 mice than in WT mice, while Prevotella abundance in WT mice was significantly higher than in APP/PS1 mice. More human studies are warranted to explore the potential of gut microbiota as diagnostic biomarkers or therapeutic target for AD. Show more

Keywords: 16S ribosomal RNA, Alzheimer’s disease, APP/PS1 mice, gut microbiota

DOI: 10.3233/JAD-160884

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 385-390, 2017

Authors: Xie, Bing | Xu, Yao | Liu, Zanchao | Liu, Wenxuan | Jiang, Lei | Zhang, Rui | Cui, Dongsheng | Zhang, Qingfu | Xu, Shunjiang

Article Type: Research Article

Abstract: Epigenetic aberrations have been identified as biomarkers to predict the risk of Alzheimer’s disease (AD). This study aimed to evaluate whether altered DNA methylation status of BDNF promoter could be used as potential epigenetic biomarkers for predicting the progression from amnestic mild cognitive impairment (aMCI) to AD. A total of 506 aMCI patients and 728 cognitively normal controls were recruited in the cross-sectional analyses. Patients (n  = 458) from aMCI cohort were classified into two groups after 5-year follow-up: aMCI-stable group (n  = 330) and AD-conversion group (n  = 128). DNA methylation of BDNF promoter was detected by bisulfite-PCR amplification and pyrosequencing. The …DNA methylation levels of CpG1 and CpG2 in promoter I and CpG5 and CpG6 in promoter IV of BDNF gene were significantly higher in the aMCI group than in the control group at baseline and also were increased in the conversion group compared with the non-conversion group at 5-year follow up time point. CpG5 in BDNF promoter IV had the highest AUC of 0.910 (95% CI: 0.817–0.983, p  < 0.05). Kaplan-Meier analysis showed a significant AD conversion propensity for aMCI patients with high methylation levels of CpG5 (HR  = 1.96, 95% CI: 1.07–2.98, p  < 0.001). Multivariate Cox regression analysis revealed elevated methylation status of CpG5 was a significant independent predictor for AD conversion (HR  = 3.51, p  = 0.013). These results suggest that elevation of peripheral BDNF promoter methylation might be used as potential epigenetic biomarkers for predicting the conversion from aMCI to AD. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, BDNF promoter, DNA methylation, follow-up study

DOI: 10.3233/JAD-160954

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 391-401, 2017

Authors: McLimans, Kelsey E. | Willette, Auriel A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Obesity and insulin resistance are associated with neuropathology and cognitive decline in Alzheimer’s disease (AD). Objective: Ecto-nucleotide pyrophosphatase/phosphodiesterase 2, also called autotaxin, is produced by beige adipose tissue, regulates metabolism, and is higher in AD prefrontal cortex (PFC). Autotaxin may be a novel biomarker of dysmetabolism and AD. Methods: We studied Alzheimer’s Disease Neuroimaging Initiative participants who were cognitively normal (CN; n  = 86) or had mild cognitive impairment (MCI; n  = 135) or AD (n  = 66). Statistical analyses were conducted using SPSS software. Multinomial regression analyses tested if higher autotaxin was associated with higher relative …risk for MCI or AD diagnosis, compared to the CN group. Linear mixed model analyses were used to regress autotaxin against MRI, FDG-PET, and cognitive outcomes. Spearman correlations were used to associate autotaxin and CSF biomarkers due to non-normality. FreeSurfer 4.3 derived mean cortical thickness in medial temporal lobe and prefrontal regions of interest. Results: Autotaxin levels were significantly higher in MCI and AD. Each point increase in log-based autotaxin corresponded to a 3.5 to 5 times higher likelihood of having MCI and AD, respectively. Higher autotaxin in AD predicted hypometabolism in the medial temporal lobe [R2  = 0.343, p  < 0.001] and PFC [R2  = 0.294, p  < 0.001], and worse performance on executive function and memory factors. Autotaxin was associated with less cortical thickness in PFC areas like orbitofrontal cortex [R2  = 0.272, p < 0.001], as well as levels of total tau, p-tau181, and total tau/Aβ1–42 . Conclusions: These results are comparable to previous reports using insulin resistance. CSF autotaxin may be a useful dysmetabolism biomarker for examining AD outcomes and risk. Show more

Keywords: Diabetes mellitus, fluorodeoxyglucose F18, insulin resistance, mild cognitive impairment, MRI, positron emission tomography

DOI: 10.3233/JAD-160891

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 403-413, 2017

Authors: Wang, Zan | Dai, Zhengjia | Shu, Hao | Liu, Duan | Guo, Qihao | He, Yong | Zhang, Zhijun

Article Type: Research Article

Abstract: Both the apolipoprotein E (APOE) ɛ 4 allele and amnestic mild cognitive impairment (aMCI) are considered to be risk factors for Alzheimer’s disease (AD). The primary aim of this study was to determine whether the aMCI-related abnormality in gray matter (GM) cortical thickness and white matter (WM) tracts integrity would be modified by the APOE genotype. A total of 146 older adults, including 64 aMCI patients (28 ɛ 4 carriers and 36 non-carriers) and 82 healthy controls (39 ɛ 4 carriers and 43 non-carriers), underwent a standardized clinical interview, neuropsychological battery assessment, and multi-modal brain magnetic resonance imaging scans. Compared …with control subjects, the patients with aMCI showed significantly reduced cortical thickness bilaterally in the parahippocampal gyrus and disrupted WM integrity in the limbic tracts (e.g., increased mean diffusivity in the right parahippocampal cingulum and bilateral uncinate fasciculus). However, no significant main effects of the APOE genotype and diagnosis-by-genotype interaction on GM thickness and WM integrity were observed. Further, diffusivity measures of the limbic WM tracts were significantly correlated with the parahippocampal atrophy in aMCI. Importantly, the parahippocampal thickness and diffusivity measures of the limbic WM tracts were significantly correlated with the cognitive performance (i.e., episodic memory Z score) in patients with aMCI. These results demonstrate that WM microstructural disruptions in the limbic tracts are present at the early stage of AD in an APOE-independent manner; and this degeneration may occur progressively, in parallel with parahippocampal atrophy, and may specifically contribute to early initial impairment in episodic memory. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, apolipoprotein E, cortical thickness, white matter integrity

DOI: 10.3233/JAD-160724

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 415-428, 2017