Journal of Alzheimer's Disease - Volume 46, issue 4

Authors: Khan, Tapan K. | Alkon, Daniel L.

Article Type: Review Article

Abstract: Widely researched Alzheimer’s disease (AD) biomarkers include in vivo brain imaging with PET and MRI, imaging of amyloid plaques, and biochemical assays of Aβ 1 - 42 , total tau, and phosphorylated tau (p-tau-181) in cerebrospinal fluid (CSF). In this review, we critically evaluate these biomarkers and discuss their clinical utility for the differential diagnosis of AD. Current AD biomarker tests are either highly invasive (requiring CSF collection) or expensive and labor-intensive (neuroimaging), making them unsuitable for use in the primary care, clinical office-based setting, or to assess drug efficacy in clinical trials. In addition, CSF and neuroimaging biomarkers continue to …face challenges in achieving required sensitivity and specificity and minimizing center-to-center variability (for CSF-Aβ 1 - 42 biomarkers CV = 26.5% ; http://www.alzforum.org/news/conference-coverage/paris-standardization-hurdle-spinal-fluid-imaging-markers ). Although potentially useful for selecting patient populations for inclusion in AD clinical trials, the utility of CSF biomarkers and neuroimaging techniques as surrogate endpoints of drug efficacy needs to be validated. Recent trials of β- and γ-secretase inhibitors and Aβ immunization-based therapies in AD showed no significant cognitive improvements, despite changes in CSF and neuroimaging biomarkers. As we learn more about the dysfunctional cellular and molecular signaling processes that occur in AD, and how these processes are manifested in tissues outside of the brain, new peripheral biomarkers may also be validated as non-invasive tests to diagnose preclinical and clinical AD. Show more

Keywords: Amyloid-β , cerebrospinal fluid biomarkers, 18FDG-PET, MRI, neuroimaging, PiB-PET, SPECT, surrogatebiomarkers, tau

DOI: 10.3233/JAD-150238

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 817-836, 2015

Authors: Asselineau, Delphine | Benlhassan, Khadija | Arosio, Beatrice | Mari, Daniela | Ferri, Evelyn | Casati, Martina | Gussago, Cristina | Tedone, Enzo | Annoni, Giorgio | Mazzola, Paolo | Piette, Francois | Belmin, Joel | Pariel, Sylvie | Bornand, Anne | Beaudeux, Jean-Louis | Doulazmi, Mohamed | Mariani, Jean | Bray, Dorothy H.

Article Type: Short Communication

Abstract: We investigated IL-10 and IL-6 production in amyloid-β (Aβ) stimulated peripheral blood mononuclear cells (PBMCs) in twenty Alzheimer’s disease (AD) patients with slow progression, eleven with fast progression, and twenty age-matched controls. Promoter polymorphisms in IL-10 (position -592, -819, -1082), IL-6 (-174), transforming growth factor-β1 (TGF-β1) (-10, -25), interferon-γ (IFN-γ ) (-874), and tumor necrosis factor-α (TNF-α ) (-308) genes were analyzed. IL-10 production after Aβ stimulation was high in PBMCs from slow decliners and almost completely abrogated in fast decliners. Association between AA IFN-γ low-producing genotype and fast progression was demonstrated. Investigations in a larger sample …will clarify these findings. Show more

Keywords: Alzheimer’s disease, disease progression, IFN-γ, interleukin-6, interleukin-10, peripheral blood mononuclear cells, single nucleotide polymorphisms

DOI: 10.3233/JAD-142832

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 837-842, 2015

Authors: Arrieta-Cruz, Isabel | Knight, Colette M. | Gutiérrez-Juárez, Roger

Article Type: Short Communication

Abstract: Patients with Alzheimer’s disease (AD) have a higher risk for developing insulin resistance and diabetes. Amyloid plaques, a hallmark of AD, are composed of amyloid-β (Aβ). Because the mediobasal hypothalamus controls hepatic glucose production, we examined the hypothesis that its exposure to Aβ perturbs the regulation of glucose metabolism. The infusion of Aβ25-35 , but not its scrambled counterpart, into the mediobasal hypothalamus of young rats, increased circulating glucose as a consequence of enhanced hepatic glucose production during pancreatic clamp studies. These findings suggest a link between AD and alterations of glucose metabolism.

Keywords: Alzheimer’s disease, amyloid-β, diabetes, glucose homeostasis, hyperglycemia, mediobasal hypothalamus

DOI: 10.3233/JAD-131865

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 843-848, 2015

Authors: Tsvetkov, Philipp O. | Cheglakov, Ivan B. | Ovsepyan, Armen A. | Mediannikov, Oleg Y. | Morozov, Alexander O. | Telegin, Georgy B. | Kozin, Sergey A.

Article Type: Short Communication

Abstract: Two tetrapeptides, HAEE and RADD, which are ionic-complementary to the primary zinc recognition site of amyloid-β (Aβ), have been reported to inhibit zinc-induced dimerization of the Aβ metal-binding domain and slow Aβ aggregation in vitro . In the present study, we investigate the impact of HAEE and RADD on the development of cerebral β-amyloidosis in a mouse model of Alzheimer’s disease. We have found chronic intravenous administration of each peptide results in significant decrease of amyloid plaque burden in the treated mice.

Keywords: Alzheimer’s disease, amyloid-β, mouse models, protein aggregation in vivo

DOI: 10.3233/JAD-150031

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 849-853, 2015

Authors: Nolze-Charron, Geneviève | Mouiha, Abderazzak | Duchesne, Simon | Bocti, Christian | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: White matter hyperintensities (WMH) may have a different impact on cognitive decline depending on strategic localization. Objective: The goal of this study is to assess the impact of global and cholinergic WMH on cognitive decline of mild cognitive impairment (MCI) patients in the ADNI-1 dataset. Methods: This is a retrospective analysis of data from a natural history study. MRI scans (T2 and PD sequences) were assessed with two visual scales: 1) The Cholinergic Pathways HyperIntensities Scale (CHIPS) score, designed to assess WMH in the cholinergic tracts, and 2) the Age-Related White …Matter Changes Scale (ARWMC), a scale to assess the global WMH burden. All subjects underwent standardized neuropsychological testing. Results: Subjects included 310 individuals with MCI. Analysis showed no association between WMH at baseline and conversion from MCI to Alzheimer’s disease (AD), either for the global WMH burden or WMH within the cholinergic pathways. However, ARWMC scores had a significant confounding effect (p  = 0.03) on conversion to dementia (hazard ratio of 0.37) among MCI subjects with low executive functions. Conclusion: We found no association between the burden of WMH at baseline in MCI and conversion to AD over 3 years. However, a higher global WMH burden appears to reduce the risk of conversion to AD in subjects with low executive functions. These results suggest that higher WMH burden in MCI individuals may be associated with a more gradual cognitive decline or stabilization, compared to a low WMH burden. Show more

Keywords: ADNI, Alzheimer’s disease, cholinergic pathways, executive functions, mild cognitive impairment, white matter hyperintensities

DOI: 10.3233/JAD-140618

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 855-862, 2015

Authors: Wu, Hao | Lu, Mei-Hong | Wang, Wang | Zhang, Mao-Ying | Zhu, Qian-Qian | Xia, Yi-Yuan | Xu, Ru-Xiang | Yang, Yi | Chen, Li-Hua | Ma, Quan-Hong

Article Type: Research Article

Abstract: Lamotrigine (LTG), a broad-spectrum anti-epileptic drug widely used in treatment for seizures, shows potential efficacy in Alzheimer’s disease (AD) therapy. Chronic LTG treatment rescues the suppressed long-term potentiation, loss of spines and cognitive deficits in AβPP/PS1 mice, known to overexpress a chimeric mouse/human mutant amyloid-β protein precursor (AβPP) and a mutant human presenilin 1 (PS1). These changes are accompanied by reduction of amyloid-β (Aβ) plaques density and of levels of β-C-terminal fragment of AβPP (β-CTF), a fragment of AβPP cleaved by β-secretase. These results suggest LTG treatment reduces Aβ production, possibly through modulation of cleavage of AβPP by β-secretase. However, …the underlying mechanisms still remain unclear. In this study, decreased protein levels, but not mRNA levels of β-site AβPP-cleaving enzyme 1 (BACE1), were observed in cultured HEK293 cells and the brains of AβPP/PS1 transgenic mice upon LTG treatment. Moreover, LTG treatment suppressed mammalian target of rapamycin (mTOR) signaling, while enhancing activation of cAMP response element binding protein (CREB), two signaling pathways essential for autophagy induction. LTG treatment increased the numbers of LC3-GFP + puncta and LC3-II levels in HEK293 cells, indicating an induction of autophagy. The downregulation of BACE1 by LTG treatment was prevented by the autophagy inhibitor 3-Methyladenine. Therefore, this study shows that LTG treatment reduces the protein levels of BACE1 through activation of autophagy, possibly via inhibition of mTOR signaling and activation of CREB. Show more

Keywords: Alzheimer’s disease, autophagy, BACE1, CREB, lamotrigine, mTOR

DOI: 10.3233/JAD-143162

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 863-876, 2015

Authors: Hansen, Henrik H. | Fabricius, Katrine | Barkholt, Pernille | Niehoff, Michael L. | Morley, John E. | Jelsing, Jacob | Pyke, Charles | Knudsen, Lotte Bjerre | Farr, Susan A. | Vrang, Niels

Article Type: Research Article

Abstract: Recent studies indicate that glucagon-like peptide 1 (GLP-1) receptor agonists, currently used in the management of type 2 diabetes, exhibit neurotrophic and neuroprotective effects in amyloid-β (Aβ) toxicity models of Alzheimer’s disease (AD). We investigated the potential pro-cognitive and neuroprotective effects of the once-daily GLP-1 receptor agonist liraglutide in senescence-accelerated mouse prone 8 (SAMP8) mice, a model of age-related sporadic AD not dominated by amyloid plaques. Six-month-old SAMP8 mice received liraglutide (100 or 500 μg/kg/day, s.c.) or vehicle once daily for 4 months. Vehicle-dosed age-matched 50% back-crossed as well as untreated young (4-month-old) SAMP8 mice were used as control groups …for normal memory function. Vehicle-dosed 10-month-old SAMP8 mice showed significant learning and memory retention deficits in an active-avoidance T-maze, as compared to both control groups. Also, 10-month-old SAMP8 mice displayed no immunohistological signatures of amyloid-β plaques or hyperphosphorylated tau, indicating the onset of cognitive deficits prior to deposition of amyloid plaques and neurofibrillary tangles in this AD model. Liraglutide significantly increased memory retention and total hippocampal CA1 pyramidal neuron numbers in SAMP8 mice, as compared to age-matched vehicle-dosed SAMP8 mice. In conclusion, liraglutide delayed or partially halted the progressive decline in memory function associated with hippocampal neuronal loss in a mouse model of pathological aging with characteristics of neurobehavioral and neuropathological impairments observed in early-stage sporadic AD. Show more

Keywords: Alzheimer’s disease, GLP-1 receptor agonist, hippocampus, liraglutide, memory function, neuroprotection, SAMP8 mouse, stereology

DOI: 10.3233/JAD-143090

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 877-888, 2015

Authors: Coart, Els | Barrado, Leandro García | Duits, Flora H. | Scheltens, Philip | van der Flier, Wiesje M. | Teunissen, Charlotte E. | van der Vies, Saskia M. | Burzykowski, Tomasz | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Studies investigating the diagnostic accuracy of biomarkers for Alzheimer’s disease (AD) are typically performed using the clinical diagnosis or amyloid-β positron emission tomography as the reference test. However, neither can be considered a gold standard or a perfect reference test for AD. Not accounting for errors in the reference test is known to cause bias in the diagnostic accuracy of biomarkers. Objective: To determine the …diagnostic accuracy of AD biomarkers while taking the imperfectness of the reference test into account. Methods: To determine the diagnostic accuracy of AD biomarkers and taking the imperfectness of the reference test into account, we have developed a Bayesian method. This method establishes the biomarkers’ true value in predicting the AD-pathology status by combining the reference test and the biomarker data with available information on the reliability of the reference test. The new methodology was applied to two clinical datasets to establish the joint accuracy of three cerebrospinal fluid biomarkers (amyloid-β 1 - 42 , Total tau, and P-tau181p ) by including the clinical diagnosis as imperfect reference test into the analysis. Results: The area under the receiver-operating-characteristics curve to discriminate between AD and controls, increases from 0.949 (with 95% credible interval [0.935,0.960]) to 0.990 ([0.985,0.995]) and from 0.870 ([0.817,0.912]) to 0.975 ([0.943,0.990]) for the cohorts, respectively. Conclusions: Use of the Bayesian methodology enables an improved estimate of the exact diagnostic value of AD biomarkers and overcomes the lack of a gold standard for AD. Using the new method will increase the diagnostic confidence for early stages of AD. Show more

Keywords: Alzheimer’s disease, Bayesian method, biomarkers, diagnostic test, reference standard

DOI: 10.3233/JAD-142886

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 889-899, 2015

Authors: Kandel, Benjamin M. | Avants, Brian B. | Gee, James C. | Arnold, Steven E. | Wolk, David A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Psychometric tests predict conversion of mild cognitive impairment (MCI) to probable Alzheimer’s disease (AD). Because the definition of clinical AD relies on those same psychometric tests, the ability of these tests to identify underlying AD pathology remains unclear. Objective: To determine the degree to which psychometric testing predicts molecular evidence of AD amyloid pathology, as indicated by cerebrospinal fluid (CSF) amyloid-β (Aβ)1 - 42 , in patients with MCI, as compared to neuroimaging biomarkers. Methods: We identified 408 MCI subjects with CSF Aβ levels, psychometric test data, FDG-PET scans, and acceptable volumetric MR …scans from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We used psychometric tests and imaging biomarkers in univariate and multivariate models to predict Aβ status. Results: The 30-min delayed recall score of the Rey Auditory Verbal Learning Test was the best predictor of Aβ status among the psychometric tests, achieving an AUC of 0.67 ± 0.02 and odds ratio of 2.5 ± 0.4. FDG-PET was the best imaging-based biomarker (AUC 0.67 ± 0.03, OR 3.2 ± 1.2), followed by hippocampal volume (AUC 0.64 ± 0.02, OR 2.4 ± 0.3). A multivariate analysis based on the psychometric tests improved on the univariate predictors, achieving an AUC of 0.68 ± 0.03 (OR 3.38 ± 1.2). Adding imaging biomarkers to the multivariate analysis did not improve the AUC. Conclusion: Psychometric tests perform as well as imaging biomarkers to predict presence of molecular markers of AD pathology in MCI patients and should be considered in the determination of the likelihood that MCI is due to AD. Show more

Keywords: Alzheimer’s disease, magnetic resonance imaging, mild cognitive impairment, positron emission tomography

DOI: 10.3233/JAD-142943

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 901-912, 2015

Authors: Khanna, Mansi R. | Fortini, Mark E.

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) is subjected to sequential intramembrane proteolysis by α -, β-, andγ -secretases, producing secreted amyloid-β (Aβ) peptides and a cytoplasmically released AβPP Intracellular Domain (AICD). AICD complexes with transcription factors in the nucleus, suggesting that this AβPP fragment serves as an active signaling effector that regulates downstream genes, although its nuclear targets are poorly defined. To further understand this potential signaling mechanism mediated by AβPP, we performed a transcriptomic identification of the Drosophila genome that is regulated by the fly AβPP orthologue in fly mushroom body neurons, which control learning- and memory-based behaviors. We …find significant changes in expression of 245 genes, representing approximately 1.6% of the Drosophila genome, with the changes ranging from +6 fold to −40 fold. The largest class of responsive targets corresponds to non-protein coding genes and includes microRNAs that have been previously implicated in Alzheimer’s disease pathophysiology. Several genes were identified in our Drosophila microarray analyses that have also emerged as putative AβPP targets in similar mammalian transcriptomic studies. Our results also indicate a role for AβPP in cellular pathways involving the regulation of Drosophila Casein Kinase II, mitochondrial oxidative phosphorylation, RNA processing, and innate immunity. Our findings provide insights into the intracellular events that are regulated by AβPP activity in healthy neurons and that might become dysregulated as a result of abnormal AβPP proteolysis in AD. Show more

Keywords: AβPP, Alzheimer’s disease, amyloid-β protein precursor, APPL, Drosophila , microarray, mushroom body, transcriptional regulation

DOI: 10.3233/JAD-141491

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 913-928, 2015