Journal of Alzheimer's Disease - Volume 69, issue 1

Authors: Li, Chenxi | Li, Youjun | Zheng, Liang | Zhu, Xiaoqi | Shao, Bixin | Fan, Geng | Liu, Tian | Wang, Jue | and Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Resting-state fMRI studies have demonstrated that Alzheimer’s disease (AD) is associated with aberrant organization and function of large-scale brain networks. However, the nature of the disruption of cross-network interactions in the key neurocognitive networks in the brain remains unclear. In this paper, we examined the ‘triple-network model’, including the default mode network (DMN), salience network (SN), and central executive network (CEN), to identify the cross-network interactions in late mild cognitive impairment (LMCI) and AD. With resting-state fMRI, we tested cross-network functional connectivity among the DMN, SN, and CEN in 33 AD patients, 24 LMCI, and 25 well-matched normal control subjects. …Then, we identified the most influential brain regions affected by AD and LMCI. Finally, we investigated the relationship between aberrant functional connectivity and clinical cognitive dysfunction. We found the cross-network functional connectivity of the SN-centered ‘triple-network model’ was significantly impaired in the AD group and the alterations were negatively correlated with the Mini-Mental State Examination (MMSE) scores. For the LMCI group, the functional connectivity of the SN-centered ‘triple-network model’ also changed compared to AD; however, we found no correlation with MMSE score. As predicted, the abnormal connections among the three networks mainly overlap with the key nodes of the three networks. Overall, our findings suggested that the interactions of the SN-centered ‘triple-network model’ are impaired in AD patients and that these alterations contribute to the decline in cognitive function. This ‘triple-network model’ provides new insights into AD and provides more information about the dysregulation of brain networks in AD. Show more

Keywords: Alzheimer’s disease, functional brain network, late mild cognitive impairment, resting-state functional MRI, triple-network model

DOI: 10.3233/JAD-181097

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 237-252, 2019

Authors: Jiang, Yanfeng | Wang, Yingzhe | Yuan, Ziyu | Xu, Kelin | Zhang, Kexun | Zhu, Zhen | Li, Peixi | Suo, Chen | Tian, Weizhong | Fan, Min | Jin, Li | Ye, Weimin | Dong, Qiang | Cui, Mei | Chen, Xingdong

Article Type: Research Article

Abstract: Individual cerebral small vessel disease (CSVD) may cause cognitive decline. However, the association between total burden of CSVD and cognitive deterioration in the general population remains unclear. We aimed to determine whether total CSVD score is associated with cognitive performance change and incident dementia in the general population. In the longitudinal population-based Taizhou Imaging Study, 556 participants free of neurological disorders underwent brain MRI and neuropsychological testing at baseline. A total of 456 participants were followed up for cognitive performance for a mean (standard deviation) of 4.6 (0.6) years. Total CSVD score (range 0–4) was calculated by assigning 1 point …for the presence of each of the following markers: lacune, white matter hyperintensity, cerebral microbleed, and perivascular space. Beta regression was used to evaluate the association between total CSVD burden and MMSE score change. The association of prevalent CSVD with incident dementia was studied using Fisher’s exact test. CSVDs were present in 262 individuals (47.1%). The total CSVD score was significantly associated with MMSE score decline (p  = 0.001). Compared to those with no CSVD, participants with 4 CSVD markers had a steeper decline in MMSE score (β : –0.53, 95% CI: –0.86 to –0.21; p  = 0.001). A total of 15 participants developed dementia during follow-up. The presence of more than three CSVD markers at baseline was associated with a significantly higher risk of dementia (p  = 0.020). Total CSVD burden appears to be associated with MMSE score decline and incident dementia in a general population in China. Show more

Keywords: Cerebral small vessel disease, cognitive dysfunction, dementia, magnetic resonance imaging

DOI: 10.3233/JAD-181135

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 253-262, 2019

Authors: Stewart, Tessandra | Shi, Min | Mehrotra, Aanchal | Aro, Patrick | Soltys, David | Kerr, Kathleen F. | Zabetian, Cyrus P. | Peskind, Elaine R. | Taylor, Peggy | Shaw, Leslie M. | Trojanowski, John Q. | Zhang, Jing | and from the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Neurodegenerative diseases require characterization based on underlying biology using biochemical biomarkers. Mixed pathology complicates discovery of biomarkers and characterization of cohorts, but inclusion of greater numbers of patients with different, related diseases with frequently co-occurring pathology could allow better accuracy. Combining cohorts collected from different studies would be a more efficient use of resources than recruiting subjects from each population of interest for each study. Objective: To explore the possibility of combining existing datasets by controlling pre-analytic variables in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Parkinson’s Progression Markers Initiative (PPMI) studies. Methods: Cerebrospinal fluid …(CSF) was collected and processed from 30 subjects according to both the ADNI and PPMI protocols. Relationships between reported levels of Alzheimer’s disease (AD) and Parkinson’s disease (PD) biomarkers in the same subject under each protocol were examined. Results: Protocol-related differences were observed for Aβ, but not t -tau or α -syn, and trended different for p -tau and pS129. Values of α -syn differed by platform. Conversion of α -syn values between ADNI and PPMI platforms did not completely eliminate differences in distribution. Discussion: Factors not captured in the pre-analytical sample handling influence reported biomarker values. Assay standardization and better harmonized characterization of cohorts should be included in future studies of CSF biomarkers. Show more

Keywords: α-Synuclein, Alzheimer’s disease, amyloid-β, Parkinson’s disease, tau

DOI: 10.3233/JAD-190069

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 263-276, 2019

Authors: Regalado-Reyes, Mamen | Furcila, Diana | Hernández, Félix | Ávila, Jesús | DeFelipe, Javier | León-Espinosa, Gonzalo

Article Type: Research Article

Abstract: Despite extensive studies regarding tau phosphorylation progression in both human Alzheimer’s disease cases and animal models, the molecular and structural changes responsible for neurofibrillary tangle development are still not well understood. Here, by using the antibodies AT100 (recognizes tau protein phosphorylated at Thr212 and Ser214 in the proline-rich region) and pS396 (recognizes tau protein phosphorylated at serine residue 396 in the C-terminal region), we examined phospho-tau immunostaining in neurons from the hippocampal CA1 region of 21 human cases with tau pathology ranging from Braak stage I to VI. Our results indicate that the AT100/pS396 ratio decreases in CA1 in accordance …with the severity of the disease, along with its colocalization. We therefore propose the AT100/pS396 ratio as a new tool to analyze the tau pathology progression. Our findings also suggest a conformational modification in tau protein that may cause the disappearance of the AT100 epitope in the late stages of tau pathology, which may play a role in the toxic tangle aggregation. Thus, this study provides new insights underlying the stages for the formation of neurofibrillary tangles in Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, hippocampus, AT100, neurofibrillary tangles, pS396, tau phosphorylation

DOI: 10.3233/JAD-181263

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 277-288, 2019

Authors: Miao, Ya | Guo, Donghao | Li, Wei | Zhong, Yuan

Article Type: Research Article

Abstract: Recent studies suggest that diabetes predisposes patients to develop neurodegenerative Alzheimer’s disease (AD), although the underlying mechanisms have yet to be determined. Compromised autophagy of neuronal cells, which occurs in the early stages of AD, has been shown to enhance disease progression. However, autophagic regulation as a mechanism connecting diabetes and AD has not been shown before. Here, we found that streptozotocin (STZ)-induced diabetic rats exhibited poorer performance on the social recognition test, Morris water maze, and plus-maze discriminative avoidance task, compared to PBS-treated normoglycemic control rats, likely resulting from increased brain deposition of amyloid-β peptide aggregates (Aβ) and increased …phosphorylation of tau protein, two pathological features of AD. Moreover, diabetes-induced AD-like behavioral and pathological changes were associated with a decrease in neuronal cell autophagy. Furthermore, compromised cell autophagy was recapitulated in vitro in neuronal cells cultured in high glucose conditions. Thus, our data suggest that hyperglycemia in diabetes may directly inhibit neuronal cell autophagy, which subsequently enhances AD-associated pathological progression. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide aggregates, autophagy, diabetes, tau

DOI: 10.3233/JAD-190156

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 289-296, 2019

Authors: Cao, Cheng | Hasegawa, Yu | Hayashi, Kenyu | Takemoto, Yushin | Kim-Mitsuyama, Shokei

Article Type: Research Article

Abstract:  Alzheimer’s disease (AD) is increasingly viewed as a neurological disease accompanied by a systemic disorder. Accumulating evidence supports that angiotensin II and angiotensin 1-7 exert opposite effects on various organs including the brain. However, the interaction between angiotensin II and angiotensin 1-7 in AD remains to be defined. The present study was undertaken to examine the interaction between these peptides in AD. 5XFAD mice, a useful model of AD, were separated into three groups: 1) saline-infused, 2) angiotensin II-infused, and 3) angiotensin II-infused and angiotensin 1-7-co-infused. These peptides were systemically given to 5XFAD mice via osmotic minipump for 4 weeks. …Systemic angiotensin II infusion for 4 weeks induced significant hypertension in both wild-type and 5XFAD mice. Angiotensin II induced cognitive abnormality in 5XFAD mice as estimated by the Morris water maze test and the nest building test, and this effect was associated with cerebral blood flow reduction, cortical arterial amyloid-β deposition, hippocampal inflammation, and neuron loss in 5XFAD mice. In addition, angiotensin II infusion led to gastrocnemius muscle atrophy in 5XFAD mice. Co-infusion of angiotensin 1-7 prevented the above mentioned detrimental effects of angiotensin II in the brain and gastrocnemius muscle in 5XFAD mice, without significant influence on blood pressure. The left ventricular hypertrophic response to angiotensin II was attenuated in 5XFAD mice compared with wild-type mice, which was not significantly altered by co-administration of angiotensin 1-7. Our results show that angiotensin 1-7 counteracts angiotensin II-induced cognitive impairment, brain injury, and skeletal muscle injury in AD mice. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, angiotensin II, angiotensin 1-7, left ventricular hypertrophy, sarcopenia

DOI: 10.3233/JAD-181000

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 297-309, 2019