Journal of Alzheimer's Disease - Volume 57, issue 1

Authors: O’Caoimh, Rónán | Gao, Yang | Svendovski, Anton | Gallagher, Paul | Eustace, Joseph | Molloy, D. William

Article Type: Research Article

Abstract: Background: Although required to improve the usability of cognitive screening instruments (CSIs), the use of cut-off scores is controversial yet poorly researched. Objective: To explore cut-off scores for two short CSIs: the Standardized Mini-Mental State Examination (SMMSE) and Quick Mild Cognitive Impairment (Qmci ) screen, describing adjustments in scores for diagnosis (MCI or dementia), age (≤, >75 years), and education (<, ≥12 years), comparing two methods: the maximal accuracy approach, derived from receiver operating characteristic curves, and Youden’s Index. Methods: Pooled analysis of assessments from patients attending memory clinics in Canada between 1999–2010 : 766 with mild …cognitive impairment (MCI) and 1,746 with dementia, and 875 normal controls. Results: The Qmci was more accurate than the SMMSE in differentiating controls from MCI or cognitive impairment (MCI and dementia). Employing the maximal accuracy approach, the optimal SMMSE cut-off for cognitive impairment was <28/30 (AUC 0.86, sensitivity 74%, specificity 88%) versus <63/100 for the Qmci (AUC 0.93, sensitivity 85%, specificity 85%). Using Youden’s Index, the optimal SMMSE cut-off remained <28/30 but fell slightly to <62/100 for the Qmci (sensitivity 83%, specificity 87%). The optimal cut-off for MCI was <29/30 for the SMMSE and <67/100 for the Qmci , irrespective of technique. The maximal accuracy approach generally produced higher Qmci cut-offs than Youden’s Index, both requiring adjustment for age and education. There were no clinically meaningful differences in SMMSE cut-off scores by age and education or method employed. Conclusion: Caution should be exercised selecting cut-offs as these differ by age, education, and method of derivation, with the extent of adjustment varying between CSIs. Show more

Keywords: Cognitive screening, cut-offs, dementia, mild cognitive impairment, Quick Mild Cognitive Impairment screen, Standardized Mini-Mental State Examination

DOI: 10.3233/JAD-161204

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 123-133, 2017

Authors: Mehta, Pankaj D. | Blain, Jean-Francois | Freeman, Emily A. | Patrick, Bruce A. | Barshatzky, Marc | Hrdlicka, Lori A. | Mehta, Sangita P. | Frackowiak, Janusz | Mazur-Kolecka, Bozena | Wegiel, Jerzy | Patzke, Holger | Miller, David L.

Article Type: Research Article

Abstract: Secreted soluble amyloid-β 1–37 (Aβ37 ) peptide is one of the prominent Aβ forms next to Aβ40 , and is found in cerebrospinal fluid (CSF) and blood. Recent studies have shown the importance of quantitation of CSF Aβ37 levels in combination with Aβ38 , Aβ40 , and Aβ42 to support the diagnosis of patients with probable Alzheimer’s disease (AD), and the value of antibody to Aβ37 to facilitate drug discovery studies. However, the availability of reliable and specific monoclonal antibody to Aβ37 is very limited. Our aims were: 1) to generate and partially characterize rabbit monoclonal …antibody (RabmAb) to Aβ37 , and 2) to determine whether the antibody detects changes in Aβ37 levels produced by a γ -secretase modulator (GSM). Our generated RabmAb to Aβ37 was found to be specific to Aβ37 , since it did not react with Aβ36 , Aβ38 , Aβ39 , Aβ40 , and Aβ42 in an ELISA or immunoblotting. The epitope of the antibody was contained in the seven C-terminal residues of Aβ37 . The antibody was sensitive enough to measure CSF and plasma Aβ37 levels in ELISA. Immunohistological studies showed the presence of Aβ37 -positive deposits in the brain of AD, and Down syndrome persons diagnosed with AD. Our studies also showed that the antibody detected Aβ37 increases in CSF and brains of rodents following treatment with a GSM. Thus, our antibody can be widely applied to AD research, and in a panel based approach it may have potential to support the diagnosis of probable AD, and in testing the effect of GSMs to target AD. Show more

Keywords: Alzheimer disease, amyloid-β peptide, Down syndrome, ELISA, immunoblotting, immunohistochemistry, rabbit monoclonal antibodies to Aβ37

DOI: 10.3233/JAD-161207

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 135-145, 2017

Authors: Rouch, Isabelle | Pongan, Elodie | Trombert, Béatrice | Fabre, Florence | Auguste, Nicolas | Sellier, Claire | Freulon, Magalie | Jacqueline, Sophie | Federico, Denis | Mouchoux, Christelle | Martin-Gaujard, Géraldine | Krolak-Salmon, Pierre | Laurent, Bernard | Dorey, Jean-Michel

Article Type: Research Article

Abstract: Background: The 2008–2012 French Alzheimer’s Plan has provided hospital Cognitive and Behavioral Units (CBU) to improve the management of patients with productive behavioral and psychological symptoms of dementia (BPSD). Little is known concerning the behavioral outcome of these patients after discharge. Objective: The present study investigated the long-term evolution of BPSD over one year after CBU discharge. Methods: The EVITAL cohort included 221 participants admitted to the CBUs of 3 French hospitals. BPSD were collected using the Neuropsychiatric Inventory (NPI) at admission and 3, 6, and 12 months after hospitalization. The global NPI score evolution …was assessed using a linear mixed-effect model. A four-factor model of the NPI including behavioral dyscontrol, psychosis, mood, and agitation subscores was also analyzed. Results: Our analysis focused on 148 patients followed up during 12 months and evaluated at each visit. The global NPI score was 48.5 (SD 21.7) at baseline, 28.8 (SD 18.7) at 3-month, 23.2 (SD 16.4) at 6-month and 20.9 (SD 15.9) at 12-month follow-up. The score significantly decreased from baseline to follow-up (F = 109.3 p  < 0.0001). Moreover, the decrease was observed for each NPI subscores. The Clinical Dementia Rating (CDR) scale score was significantly linked to the baseline NPI score (t  = 2.76, p  = 0.009). Conversely, the NPI decline was observed whatever the CDR level. Conclusion: The present study showed a decrease in the global NPI score and all its subscores during the year following the CBU hospitalization, regardless of the initial CDR score. Show more

Keywords: Alzheimer’s disease, behavioral disorders, BPSD, dementia, longitudinal study

DOI: 10.3233/JAD-161023

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 147-155, 2017

Authors: Yang, Jing | Zhang, Rui | Shi, Changhe | Mao, Chengyuan | Yang, Zhihua | Suo, Zhenhe | Torp, Reidun | Xu, Yuming

Article Type: Research Article

Abstract: Amyloid-β deposition in senile plaques is one of the main pathological changes in Alzheimer’s disease (AD). We previously reported that aquaporin-4 (AQP4) is redistributed within the astrocytes in cerebral amyloid angiopathy in the tg-ArcSwe mouse model of AD, suggesting that AQP4 may participate in amyloid-β deposition. However, the role of AQP4 in plaque formation is not currently clear. The objective of the current study was to explore the AQP4 distribution within plaques in the tg-ArcSwe mice in more depth by the combined application of immunofluorescence cytochemistry and immunogold electron microscopy. In addition, the astrocyte marker, glial fibrillary acidic protein (GFAP), …was studied in association with AQP4. We demonstrated a robust upregulation of AQP4 expression in areas of plaques. Compared to GFAP, AQP4 appeared predominantly at later stages of plaque formation, in older mice, and within the processes of astrocytes. In combination with GFAP, AQP4 differentiated plaques into three progression stages under light microscopy. This suggests that AQP4 expression was associated with amyloid deposition and astrocyte pathology in the Tg-ArcSwe mouse model of AD. This provides novel proof for the involvement of AQP4 in the process of amyloid deposition in AD. Show more

Keywords: Alzheimer’s disease, aquaporin 4, astrocyte, glial fibrillary acidic protein, senile plaques

DOI: 10.3233/JAD-160957

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 157-169, 2017

Authors: Yamazaki, Kiyohiro | Yoshino, Yuta | Mori, Takaaki | Yoshida, Taku | Ozaki, Yuki | Sao, Tomoko | Mori, Yoko | Ochi, Shinichiro | Iga, Jun-ichi | Ueno, Shu-ichi

Article Type: Research Article

Abstract: Background/Objective: The aim of this study was to examine the blood gene expression and methylation of ATP-binding cassette sub-family A member 7 gene (ABCA7) as a biological marker of AD. Methods: AD subjects (n  = 50; 11 males, 77.7±6.05 years old) and age- and sex-matched healthy controls (n  = 50) were recruited. A single nucleotide polymorphism in ABCA7 (rs3764650), methylation rates of CpG sites in the ABCA7 promoter region, and ABCA7 mRNA expression levels in peripheral blood were examined. Results: The distribution of the rs3764650 polymorphism in AD subjects was not different from that of controls. Although …the methylation rates of AD subjects were not significantly different from those of controls, the ABCA7 mRNA expression level in AD subjects was significantly higher than that in controls. Additionally, the ABCA7 mRNA expression level in AD subjects was significantly correlated with Mini-Mental State Examination recall, the Alzheimer’s Disease Assessment Scale total score, and the Clinical Dementia Rating score. We also found a significant correlation between the ABCA7 mRNA expression level and duration of illness. Conclusion: The ABCA7 mRNA expression level in peripheral blood may be a marker for early stages of AD and disease progression regardless of rs3764650 and the methylation rate of its promoter. Show more

Keywords: Alzheimer’s disease, ATP-binding cassette sub-family A member 7 gene, epigenetics, mRNA, single nucleotide polymorphism

DOI: 10.3233/JAD-161195

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 171-181, 2017

Authors: Cardoso, Bárbara R. | Hare, Dominic J. | Bush, Ashley I. | Li, Qiao-Xin | Fowler, Christopher J. | Masters, Colin L. | Martins, Ralph N. | Ganio, Katherine | Lothian, Amber | Mukherjee, Soumya | Kapp, Eugene A. | Roberts, Blaine R. | The AIBL research group

Article Type: Research Article

Abstract: Selenium (Se) protects cells against oxidative stress damage through a range of bioactive selenoproteins. Increased oxidative stress is a prominent feature of Alzheimer’s disease (AD), and previous studies have shown that Se deficiency is associated with age-related cognitive decline. In this study, we assessed Se status in different biofluids from a subgroup of participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. As Se in humans can either be an active component of selenoproteins or inactive via non-specific incorporation into other proteins, we used both size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) and tandem mass spectrometry …to characterize selenoproteins in serum. We observed no differences in total Se concentration in serum or cerebrospinal fluid of AD subjects compared to mildly cognitively impairment patients and healthy controls. However, Se levels in erythrocytes were decreased in AD compared to controls. SEC-ICP-MS analysis revealed a dominant Se-containing fraction. This fraction was subjected to standard protein purification and a bottom-up proteomics approach to confirm that the abundant Se in the fraction was due, in part, to selenoprotein P. The lack of change in the Se level is at odds with our previous observations in a Brazilian population deficient in Se, and we attribute this to the Australian cohort being Se-replete. Show more

Keywords: Alzheimer’s disease, cognition, selenium, selenocysteine, selenoproteins

DOI: 10.3233/JAD-160622

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 183-193, 2017

Authors: Meyer, Michelle L. | Palta, Priya | Tanaka, Hirofumi | Deal, Jennifer A. | Wright, Jacqueline | Knopman, David S. | Griswold, Michael E. | Mosley, Thomas H. | Heiss, Gerardo

Article Type: Research Article

Abstract: Background: The association of central arterial stiffness and pressure pulsatility with mild cognitive impairment (MCI) and dementia is not well characterized in the population-based setting. Objective: The aim of this study was to quantify the cross-sectional association of arterial stiffness and pressure pulsatility with MCI and dementia among 4,461 older white and black adults from the population-based Atherosclerosis Risk in Communities Study-Neurocognitive Study. Methods: We used race-stratified multinomial logistic regression to evaluate associations of percentile cut points of carotid-femoral pulse wave velocity, central systolic blood pressure, central pulse pressure, and pulse pressure amplification with MCI …and dementia versus no cognitive impairment. Results: Among whites, those with carotid-femoral pulse wave velocity or central systolic blood pressure ≥75th percentile had a higher prevalence of MCI compared to participants <75th percentile (conditional odds ratio (OR); 95% confidence interval (CI): 1.27 (1.02, 1.56) and 1.28 (1.04, 1.57), respectively) and those with central pulse pressure ≥75th percentile had a higher prevalence of MCI (OR 1.27 (95% CI: 1.03, 1.58)) and dementia (OR 1.76 (95% CI: 1.06, 2.92) compared to participants <75th percentile. Also among whites, those with pulse pressure amplification ≤25th percentile had a higher prevalence of dementia compared to participants >25th percentile (OR 1.65; (95% CI: 1.01, 2.70). Weaker associations were seen among black participants. Conclusion: Higher arterial stiffness and pulsatility were associated with MCI and dementia in white participants. Longitudinal characterization of the observed associations is warranted to assess whether arterial stiffness and pressure pulsatility predict MCI and dementia among older adults. Show more

Keywords: Alzheimer’s disease, brain, cognition, dementia, mild cognitive impairment, pulse wave velocity

DOI: 10.3233/JAD-161041

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 195-204, 2017

Authors: Salgado-Puga, Karla | Rodríguez-Colorado, Javier | Prado-Alcalá, Roberto A. | Peña-Ortega, Fernando

Article Type: Research Article

Abstract: In addition to coupling cell metabolism and excitability, ATP-sensitive potassium channels (KATP ) are involved in neural function and plasticity. Moreover, alterations in KATP activity and expression have been observed in Alzheimer’s disease (AD) and during amyloid-β (Aβ)-induced pathology. Thus, we tested whether KATP modulators can influence Aβ-induced deleterious effects on memory, hippocampal network function, and plasticity. We found that treating animals with subclinical doses (those that did not change glycemia) of a KATP blocker (Tolbutamide) or a KATP opener (Diazoxide) differentially restrained Aβ-induced memory deficit, hippocampal network activity inhibition, and long-term synaptic plasticity unbalance (i.e., …inhibition of LTP and promotion of LTD). We found that the protective effect of Tolbutamide against Aβ-induced memory deficit was strong and correlated with the reestablishment of synaptic plasticity balance, whereas Diazoxide treatment produced a mild protection against Aβ-induced memory deficit, which was not related to a complete reestablishment of synaptic plasticity balance. Interestingly, treatment with both KATP modulators renders the hippocampus resistant to Aβ-induced inhibition of hippocampal network activity. These findings indicate that KATP are involved in Aβ-induced pathology and they heighten the potential role of KATP modulation as a plausible therapeutic strategy against AD. Show more

Keywords: Amyloid-β protein, burrowing, hippocampal population activity, learning and memory, long-term depression, long-term potentiation, sulphonylurea

DOI: 10.3233/JAD-160543

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 205-226, 2017

Authors: Wang, Jianhui | Liu, Yang | Cheng, Xiaorui | Zhang, Xiaorui | Liu, Feng | Liu, Gang | Qiao, Shanyi | Ni, Ming | Zhou, Wenxia | Zhang, Yongxiang | Li, Fei

Article Type: Research Article

Abstract: The senescence-accelerated mouse prone 8 (SAMP8) strain is considered a robust experimental model for developing preventative and therapeutic treatments for Alzheimer’s disease (AD), a neurodegenerative disease which cannot be effectively prevented, halted, or cured. Our previous studies showed that LW-AFC, a new formula derived from the classical traditional Chinese medicinal prescription Liuwei Dihuang decoction, ameliorates cognitive deterioration in PrP-hAβPPswe/PS1Δ E9 transgenic mice and SAMP8 mice. This study aims to investigate the mechanism that mediates how LW-AFC improves cognitive deficit on the basis of the transcriptome. We conducted a genome-wide survey of gene expression in the hippocampus in mice from …the senescence accelerated mouse resistant 1 (SAMR1) strain, from SAMP8 and from LW-AFC treated SAMP8. The results showed that LW-AFC reversed the transcriptome in the hippocampus of SAMP8 mice. The specific investigation of altered gene expression in subtypes defined by cognitive profiles indicated that the systemic lupus erythematosus pathway, spliceosomes, amyotrophic lateral sclerosis, and the insulin signaling were involved in the improvement of cognitive ability by LW-AFC. The expression of genes Enpp2, Etnk1, Epdr1, and Gm5900 in the hippocampus were correlated with that of LW-AFC’s ameliorating cognitive impairment in SAMP8 mice. Because LW-AFC is composed of polysaccharides, glycosides, and oligosaccharides, we infer that LW-AFC has direct or indirect effects on altering gene expressions and regulating pathways in the hippocampus of SAMP8 mice. These data are helpful for the enhanced identification of LW-AFC as new therapeutic modalities to AD. Show more

Keywords: Alzheimer’s disease, LW-AFC, senescence-accelerated mouse prone 8 strain, traditional Chinese medicine, transcriptome

DOI: 10.3233/JAD-161079

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 227-240, 2017

Authors: Rhea, Elizabeth M. | Humann, Samantha R. | Nirkhe, Surabhi | Farr, Susan A. | Morley, John E. | Banks, William A.

Article Type: Research Article

Abstract: Insulin delivered to the level of the cribriform plate (intranasal insulin) is being investigated for its ability to enhance memory in people with Alzheimer’s disease (AD). Recent work has shown intranasal insulin can be detected in young CD-1 mice within 5 min and is still present 60 min after injection. The current study determined whether intranasal insulin transport and the subsequent brain distribution of insulin varies in young, healthy mice (CD-1) compared to those with an AD-like phenotype (aged SAMP8) or those pre-disposed to develop such a phenotype (young SAMP8). We showed transport does not vary among these three mouse cohorts, suggesting …that intranasal uptake and brain pharmacokinetics do not differ with AD-like signs or the genetic predisposition to developing them. We found that co-administration with bovine serum albumin increased levels of insulin in most brain regions. In addition, the insulin receptor inhibitor, S961, decreases the amount of insulin transported throughout the brain after intranasal injection. These results show insulin delivery to the brain by intranasal administration can be modified with agents such as albumin, may be dependent on the insulin receptor, and is not affected by an AD-like phenotype as presented by the SAMP8 mouse. Show more

Keywords: Alzheimer’s disease, insulin, intranasal administration, pharmacokinetics

DOI: 10.3233/JAD-161095

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 241-252, 2017