Journal of Alzheimer's Disease - Volume 65, issue 4

Authors: Dang, Christa | Harrington, Karra D. | Lim, Yen Ying | Ames, David | Hassenstab, Jason | Laws, Simon M. | Yassi, Nawaf | Hickey, Martha | Rainey-Smith, Stephanie | Robertson, Joanne | Sohrabi, Hamid R. | Salvado, Olivier | Weinborn, Michael | Villemagne, Victor L. | Rowe, Christopher C. | Masters, Colin L. | Maruff, Paul | for the AIBL Research Group

Article Type: Research Article

Abstract: Background: Preclinical Alzheimer’s disease (AD) is defined by cerebral amyloid-β positivity (Aβ+) in cognitively normal (CN) older adults. Objective: To estimate the risk of progression to the symptomatic stages of AD due to PET Aβ+ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study. Methods: Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to Aβ+, APOE ɛ 4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n  = 599) …over 8 years. Results: 17.7% Aβ+ and 8.1% Aβ–progressed over 8 years (OR: 2.43). Risk of progression for Aβ+ was 65–104% greater than Aβ–. Aβ+ APOE ɛ 4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in Aβ+ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ɛ 4 carriage (HR: 2.63); only age was a significant risk factor in Aβ–(HR: 1.09). Aβ–progressors were not near the threshold for Aβ+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA. Conclusion: Aβ+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOE ɛ 4 carriage provides further predictive value in the presence of Aβ+. These data suggest that Aβ-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated Aβ deposition may be the result of neuropathological processes other than AD that accumulate with age. Show more

Keywords: Alzheimer’s disease, APOE ɛ4, biomarkers, dementia, mild cognitive impairment

DOI: 10.3233/JAD-180507

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1313-1325, 2018

Authors: Ismail, Sanda | Christopher, Gary | Dodd, Emily | Wildschut, Tim | Sedikides, Constantine | Ingram, Tom A. | Jones, Roy W. | Noonan, Krist A. | Tingley, Danielle | Cheston, Richard

Article Type: Research Article

Abstract: Background: Studies with non-clinical populations show that nostalgia increases psychological resources, such as self-esteem and social connectedness. Objectives: Our objectives were to find out if the benefits of nostalgia in non-clinical populations generalize to people with dementia and if nostalgia facilitates recall of dementia-related information. Methods: All three experiments recruited participants with mild or moderate levels of dementia. Experiment 1 tested whether nostalgia (compared to control) enhances psychological resources among 27 participants. Experiment 2 used music to induce nostalgia (compared to control) in 29 participants. Experiment 3 compared recall for self-referent dementia statements among 50 participants …randomized to either a nostalgia or control condition. Findings across experiments were synthesized with integrative data analysis. Results: Nostalgia (compared to control) significantly increased self-reported social connectedness, meaning in life, self-continuity, optimism, self-esteem, and positive (but not negative) affect (Experiments 1–3). Compared to controls, nostalgic participants also recalled significantly more self-referent dementia-related information (Experiment 3). Conclusion: This series of experiments extends social psychological research with non-clinical populations into dementia care, providing evidence that nostalgia significantly enhances psychological resources. The finding that nostalgia increased recall of self-referent statements about dementia suggests that this emotion lends participants the fortitude to face the threat posed by their illness. The finding has potentially important clinical implications both for the development of reminiscence therapy and for facilitating adjustment to a diagnosis of dementia. Show more

Keywords: Alzheimer’s disease, autobiographical memory, dementia, immediate recall, psychological adaptation

DOI: 10.3233/JAD-180075

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1327-1344, 2018

Authors: Ramanan, Vijay K. | Przybelski, Scott A. | Graff-Radford, Jonathan | Castillo, Anna M. | Lowe, Val J. | Mielke, Michelle M. | Roberts, Rosebud O. | Reid, Robert I. | Knopman, David S. | Jack Jr., Clifford R. | Petersen, Ronald C. | Vemuri, Prashanthi

Article Type: Research Article

Abstract: Background: Statins have been proposed to reduce the risk of Alzheimer’s disease (AD). Objective: Assess whether long-term statin use was associated with neuroimaging biomarkers of aging and dementia. Methods: Methods: We analyzed neuroimaging biomarkers in 1,160 individuals aged 65+ from the Mayo Clinic Study of Aging, a population-based prospective longitudinal study of cognitive aging. Results: Statin-treated (5+ years of therapy) individuals had greater burden of mid-and late-life cardiovascular disease (p  < 0.001) than statin-untreated (≤3 months) individuals. Lower fractional anisotropy in the genu of the corpus callosum, an early marker of cerebrovascular disease, was associated …with long-term statin exposure (p  < 0.035). No significant associations were identified between long-term statin exposure and cerebral amyloid or tau burden, AD pattern neurodegeneration, or white matter hyperintensity burden. Conclusions: Long-term statin therapy was not associated with differences in AD biomarkers. Individuals with long-term statin exposure had worse white matter integrity in the genu of the corpus callosum, consistent with the coexistence of higher cerebrovascular risk factor burden in this group. Show more

Keywords: Alzheimer’s disease, amyloid, neurodegeneration, cerebrovascular disease, biomarkers, magnetic resonance imaging, positron emission tomography, statins, tau, white matter

DOI: 10.3233/JAD-180446

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1345-1352, 2018

Authors: Liang, Jia-Wei | Fang, Zheng-Yu | Huang, Yong | Liuyang, Zhen-yu | Zhang, Xiao-Lin | Wang, Jing-Lin | Wei, Hui | Wang, Jian-Zhi | Wang, Xiao-Chuan | Zeng, Ji | Liu, Rong

Article Type: Research Article

Abstract: Background: Weighted co-expression network analysis (WGCNA) is a powerful systems biology method to describe the correlation of gene expression based on the microarray database, which can be used to facilitate the discovery of therapeutic targets or candidate biomarkers in diseases. Objective: To explore the key genes in the development of Alzheimer’s disease (AD) by using WGCNA. Methods: The whole gene expression data GSE1297 from AD and control human hippocampus was obtained from the GEO database in NCBI. Co-expressed genes were clustered into different modules. Modules of interest were identified through calculating the correlation coefficient between the …module and phenotypic traits. GO and pathway enrichment analyses were conducted, and the central players (key hub genes) within the modules of interest were identified through network analysis. The expression of the identified key genes was confirmed in AD transgenic mice through using qRT-PCR. Results: Two modules were found to be associated with AD clinical severity, which functioning mainly in mineral absorption, NF-κ B signaling, and cGMP-PKG signaling pathways. Through analysis of the two modules, we found that metallothionein (MT), Notch2, MSX1, ADD3, and RAB31 were highly correlated with AD phenotype. Increase in expression of these genes was confirmed in aged AD transgenic mice. Conclusion: WGCNA analysis can be used to analyze and predict the key genes in AD. MT1 , MT2 , MSX1, NOTCH2 , ADD3, and RAB31 are identified to be the most relevant genes, which may be potential targets for AD therapy. Show more

Keywords: ADD3, Alzheimer’s disease, metallothionein, MSX1, Notch2, neurofibrillary tangles, RAB31, WGCNA

DOI: 10.3233/JAD-180400

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1353-1364, 2018

Authors: Tene, Oren | Hallevi, Hen | Korczyn, Amos D. | Shopin, Ludmila | Molad, Jeremy | Kirschbaum, Clemens | Bornstein, Natan M. | Shenhar-Tsarfaty, Shani | Kliper, Efrat | Auriel, Eitan | Usher, Sali | Stalder, Tobias | Ben Assayag, Einor

Article Type: Research Article

Abstract: Background and Objective: Previous studies suggest that excessive cortisol levels after stroke are associated with cognitive dysfunction. However, limited data exist regarding associations between post-stroke cortisol levels, brain abnormalities, genetic factors, and cognitive outcome. We sought to study these issues in a longitudinal stroke survivors cohort. Methods: Data from 182 cognitively intact ischemic stroke patients from the TABASCO study were available. Saliva cortisol levels (bedtime and post-awakening) and cognitive assessments were obtained on admission, and 6, 12, and 24 months thereafter. During hospitalization, patients underwent 3T MRI scans and APOE genotyping. Results: Higher bedtime cortisol levels …immediately post-stroke were associated with larger neurological deficits (p  < 0.001), brain atrophy (p  = 0.025), worse white matter integrity (p  = 0.003), and worse cognitive results up to 24 months post-stroke. These findings remained significant when adjusted for age, gender, education, smoking, stroke severity, apolipoprotein E4 (ApoE4) status, and body mass index. ApoE4 negatively modified the relation between cortisol and memory. As a group, participants who presented with high admission bedtime cortisol levels continued to present relatively elevated bedtime levels across all examined time-points, and this group had inferior memory and executive functioning scores compared to the lower cortisol group 24 months post-stroke (p  = 0.05, p  = 0.035, respectively). Post-awakening cortisol levels were not associated with neuroimaging findings or cognitive scores. Conclusions: High bedtime salivary cortisol levels post-stroke may provide information about dysregulation of diurnal HPA-axis activity under acute challenge conditions, and predict worse cognitive outcome. ApoE4 genotype might modify this association. These findings call for specific stress management interventions in stroke survivors. Show more

Keywords: ApoE4, brain atrophy, cognitive impairment, HPA axis, salivary cortisol, stroke

DOI: 10.3233/JAD-180486

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1365-1375, 2018

Authors: Koychev, Ivan | Galna, Brook | Zetterberg, Henrik | Lawson, Jennifer | Zamboni, Giovanna | Ridha, Basil H. | Rowe, James B. | Thomas, Alan | Howard, Robert | Malhotra, Paresh | Ritchie, Craig | Lovestone, Simon | Rochester, Lynn

Article Type: Research Article

Abstract: Gait disturbances are some of the earliest changes in dementia and their monitoring presents an opportunity for early diagnosis. The exact relationship between gait and well-established biomarkers of Alzheimer’s disease (AD) remains to be clarified. In this study we compared gait-related measures with cerebrospinal fluid (CSF) markers of AD pathology. We recruited seventeen participants with mild AD in a multi-site study and performed gait assessment as well as lumbar punctures to obtain CSF. CSF Aβ42 /Aβ40 and Aβ42 /Aβ38 correlated positively with measures of variability (step time and step length) in the clinic-based assessments. This was driven by …a negative relationship between gait variability and Aβ40 and Aβ38 but not Aβ42 .The amyloid ratios and gait variability measures were also associated with more severe functional impairment. We interpret these data as an indication that increasing amyloid production (i.e., increasing Aβ40 and Aβ38 ) is associated with diminishing cognitive-motor control of gait. These preliminary results suggest that the two amyloid ratios may be a marker of the earliest disturbances in the interplay between cognitive and motor control which characterize dementia. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid proteins, gait

DOI: 10.3233/JAD-180622

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1377-1383, 2018

Authors: Wang, Shanshan | He, Benhong | Hang, Weijian | Wu, NingHua | Xia, Liangtao | Wang, Xu | Zhang, Qianying | Zhou, Xinwen | Feng, Zuohua | Chen, Qingjie | Chen, Juan

Article Type: Research Article

Abstract: Background: Axonopathy is closely linked to the development of diabetic encephalopathy induced by type II diabetes (T2D). Berberine has been shown to cross the blood-brain barrier and holds promising effect for neuronal damage in diabetes. Objective: The present study investigated the protective effect and the underlying mechanism of berberine on neuronal axonopathy in both in vitro and in vivo models. Methods: High glucose/high fat diet and streptozotocin injection-induced T2D rat model was used. Berberine was administered p.o. to T2D rat model for 10 weeks. Morris water maze test, in vivo neuronal tracing, immunohistochemistry, …and western blot analysis were performed to evaluate the protective effects of berberine in T2D-induced diabetic encephalopathy rats. Primary cultured neurons were used to further explore the underlying mechanisms in vitro . Results: Berberine dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Berberine significantly attenuated memory impairment, axonopathy, and tau hyperphosphorylation, and also restored PI3K/Akt/GSK3β signaling pathway in T2D rats. In vitro , berberine induced an increase in the phosphorylation of PI3K/Akt as well as GSK3β in high glucose-treated primary neurons. Furthermore, berberine-induced PI3K/Akt activation also resulted in the dephosphorylation of tau protein, which could improve axonal transport impairment in high glucose-treated primary neurons. Pretreated neurons with LY294002, an inhibitor of PI3K, partially blocked berberine-inhibited tau phosphorylation and berberine-activated PI3K/Akt signaling pathway. Conclusions: Berberine exerts the protective effect against cognitive deficits by improving tau hyperphosphorylation and the axonal damage through restoring PI3K/Akt/GSK3β signaling pathway. Show more

Keywords: Axonopathy, berberine, diabetic encephalopathy, insulin, tau phosphorylation

DOI: 10.3233/JAD-180497

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1385-1400, 2018

Authors: Huan, Tao | Tran, Tran | Zheng, Jiamin | Sapkota, Shraddha | MacDonald, Stuart W. | Camicioli, Richard | Dixon, Roger A. | Li, Liang

Article Type: Research Article

Abstract: Using a non-invasive biofluid (saliva), we apply a powerful metabolomics workflow for unbiased biomarker discovery in Alzheimer’s disease (AD). We profile and differentiate Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD groups. The workflow involves differential chemical isotope labeling liquid chromatography mass spectrometry using dansylation derivatization for in-depth profiling of the amine/phenol submetabolome. The total sample (N  = 109) was divided in to the Discovery Phase (DP) (n  = 82; 35 CN, 25 MCI, 22 AD) and a provisional Validation Phase (VP) (n  = 27; 10 CN, 10 MCI, 7 AD). In DP we detected 6,230 metabolites. Pairwise analyses confirmed biomarkers for …AD versus CN (63), AD versus MCI (47), and MCI versus CN (2). We then determined the top discriminating biomarkers and diagnostic panels. A 3-metabolite panel distinguished AD from CN and MCI (DP and VP: Area Under the Curve [AUC] = 1.000). The MCI and CN groups were best discriminated with a 2-metabolite panel (DP: AUC = 0.779; VP: AUC = 0.889). In addition, using positively confirmed metabolites, we were able to distinguish AD from CN and MCI with good diagnostic performance (AUC > 0.8). Saliva is a promising biofluid for both unbiased and targeted AD biomarker discovery and mechanism detection. Given its wide availability and convenient accessibility, saliva is a biofluid that can promote diversification of global AD biomarker research. Show more

Keywords: Alzheimer’s disease, biomarkers, liquid chromatography mass spectrometry, metabolomics, saliva, Victoria Longitudinal Study

DOI: 10.3233/JAD-180711

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1401-1416, 2018

Authors: Tariciotti, Leonardo | Casadei, Matthew | Honig, Lawrence S. | Teich, Andrew F. | McKhann II, Guy M. | Tosto, Giuseppe | Mayeux, Richard

Article Type: Research Article

Abstract: Background: Elevated total tau (tTau), 181-phosphorylated phosphorylated tau (pTau), and low amyloid-β42 (Aβ42 ) in cerebrospinal fluid (CSF) represent a diagnostic biomarker for Alzheimer’s disease (AD). Objective: The goal was to determine the overall accuracy of CSF Aβ42 , tTau, pTau, and the Aβ42 /total tau index (ATI) in a non-research, clinical setting for the diagnosis of AD. Methods: From medical records in 1,016 patients that had CSF studies for dementia over a 12-year period (2005 to 2017), we calculated the sensitivity and specificity of CSF Aβ42 , tTau, and pTau and …the ATI in relation to the final clinical diagnosis. Results: Compared with non-demented patients and patients with other dementias or mild cognitive impairment (MCI), the sensitivity and specificity of the recommended ATI and pTau cut-offs (ATI < 1.0 and pTau >61 pg/ml) for the diagnosis of AD were 0.88 and 0.72, respectively. Similar results were obtained comparing AD with non-demented patients only (0.88, 0.82) and AD with other types of dementia (0.81, 0.77). A subgroup of patients with presumed normal pressure hydrocephalus (n  = 154) were biopsied at the time of shunt placement. Using the pathological manifestations of AD as the standard, the sensitivity was 0.83 while the specificity was 0.72. Conclusions: In a non-research setting, CSF biomarkers for AD showed a high sensitivity in accordance with previous studies, but modest specificity differentiating AD from other types of dementia or MCI. This study of unselected patients provides a valid and realistic assessment of the diagnostic accuracy of these CSF biomarkers in clinical practice. Show more

Keywords: Aβ42 , accuracy, Alzheimer’s disease, CSF biomarkers, pTau, sensitivity, specificity, tTau

DOI: 10.3233/JAD-180548

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1417-1425, 2018

Authors: Crunfli, Fernanda | Mazucanti, Caio Henrique | de Moraes, Ruan Carlos Macêdo | Costa, Andressa Pereira | Rodrigues, Alice Cristina | Scavone, Cristoforo | Torrão, Andréa da Silva

Article Type: Research Article

Abstract: Sporadic Alzheimer’s disease (sAD) is associated with energy metabolism deficiency and impairment of insulin receptor (IR) signaling in the brain. In this context, low doses of intracerebroventricular (icv) injection of streptozotocin (STZ) in rodents has been used as an experimental model of sAD which leads to an insulin-resistant brain state and neurodegeneration. However, the STZ effects on brain insulin signaling-related proteins it is not appropriately elucidated. The aim of this study was to evaluate the beginning and progression of alterations in the brain IR pathway of rats after 1, 3, 5, and 7 days of STZ injection and investigate intracellular …signaling involved on STZ induced insulin resistance. We observed that STZ injection causes cognitive impairment in the animals, a temporal variation of the insulin signaling-related proteins and apoptosis cell death in the hippocampus. We also have shown that STZ causes insulin resistance and impairment on phosphoinositide 3-kinase (PI3K) activity in the Neuro-2a cells through protein kinase B (Akt) inactivation by S-nitrosylation, which could upregulate GSK3-β activity. STZ ability to cause an insulin-resistant neuron state involves NO production and ROS production which may play an important role in the mechanism linked to STZ-induced neurotoxicity. The icv injection of STZ model and STZ exposed Neuro-2a cells may be potential experimental models for assessing molecules related to the pathogenesis of sAD. Show more

Keywords: Alzheimer’s disease, Akt, insulin resistance, nitric oxide, streptozotocin

DOI: 10.3233/JAD-180284

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1427-1443, 2018