Journal of Alzheimer's Disease - Volume 45, issue 4

Authors: Wright, John W. | Harding, Joseph W.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease increasing in frequency as life expectancy of the world's population increases. There are an estimated 5 million diagnosed AD patients in the U.S. and 16 million worldwide with no adequate treatment presently available. New therapeutic approaches are needed to slow, and hopefully reverse, disease progression. This review summarizes available information regarding an overlooked therapeutic target that may offer a treatment to slow and hopefully halt AD, namely the hepatocyte growth factor (HGF)/c-Met receptor system. Activation of the c-Met receptor stimulates mitogenesis, motogenesis, morphogenesis, the ability to mediate stem cell differentiation and neurogenesis, …and protects against tissue insults in a wide range of cells including neurons. This growth factor system has recently been shown to induce dendritic arborization and synaptogenesis when stimulated by a newly developed angiotensin-based analogue, N-hexanoic-Tyr-Ile-(6) amino hexanoic amide (Dihexa). This small molecule was derived from the pre-prototype molecule Nle1 -angiotensin IV and has shown promise in facilitating the formation of new functional synaptic connections and augmenting memory consolidation in animal models of AD. Dihexa is a first-in-class compound that is orally active, penetrates the blood-brain barrier, and facilitates memory consolidation and retrieval. This angiotensin-based small molecule may be efficacious as a treatment for AD. Show more

Keywords: Alzheimer's disease, angiotensin IV, AT4 receptor subtype, c-Met receptor, Dihexa, hepatocyte growth factor, Nle1-Angiotensin IV

DOI: 10.3233/JAD-142814

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 985-1000, 2015

Authors: Bouvier, David S. | Murai, Keith K.

Article Type: Review Article

Abstract: Microglia and astrocytes are essential components of brain homeostasis. Interestingly, when the brain is exposed to adverse conditions, both astrocytes and microglia acquire specialized ‘reactive’ or ‘activated’ phenotypes that relate to the characteristics of the insult. In most cases they become important perpetrators of inflammation and potentially neuronal dysfunction. In neurodegenerative diseases such as Alzheimer's disease, the reciprocal interactions between microglia and astrocytes may be particularly important for the development of neuronal pathology and disease states. An important challenge is to understand how microglia and astrocytes inter-communicate at different stages of disease and the importance of this crosstalk on the …physiology of surrounding neurons. In this review we focus on the potential roles that microglia and astrocytes fulfill in early to late stages of AD and how their synergistic actions may shape the progression of AD pathology to affect brain health. Show more

Keywords: Activation, degeneration, glia, inflammation, plaque, reactivity

DOI: 10.3233/JAD-143156

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1001-1014, 2015

Authors: Bouleau, Sylvina | Tricoire, Hervé

Article Type: Review Article

Abstract: Amyloid-β protein precursor (AβPP) and the microtubule-associated protein tau (MAPT) are the two key players involved in Alzheimer's disease (AD) and are associated with amyloid plaques and neurofibrillary tangles respectively, two key hallmarks of the disease. Besides vertebrate models, Drosophila models have been widely used to understand the complex events leading to AD in relation to aging. Drosophila benefits from the low redundancy of the genome which greatly simplifies the analysis of single gene disruption, sophisticated molecular genetic tools, and reduced cost compared to mammals. The aim of this review is to describe the recent advances in modeling AD using …fly and to emphasize some limits of these models. Genetic studies in Drosophila have revealed some key aspects of the normal function of Appl and Tau, the fly homologues of AβPP and MAPT that may be disrupted during AD. Drosophila models have also been useful to uncover or validate several pathological pathways or susceptibility genes, and have been readily implemented in drug screening pipelines. We discuss some limitations of the current models that may arise from differences in structure of Appl and Tau compared to their human counterparts or from missing AβPP or MAPT protein interactors in flies. The advent of new genome modification technologies should allow the development of more realistic fly models and to better understand the relationship between AD and aging, taking advantage of the fly's short lifespan. Show more

Keywords: Aging, Alzheimer's disease, amyloid beta-peptides, amyloid beta-protein precursor, disease models, Drosophila, nerve degeneration, tau proteins, tauopathy

DOI: 10.3233/JAD-142802

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1015-1038, 2015

Authors: Niemantsverdriet, Ellis | Feyen, Bart F.E. | Le Bastard, Nathalie | Martin, Jean-Jacques | Goeman, Johan | De Deyn, Peter Paul | Engelborghs, Sebastiaan

Article Type: Short Communication

Abstract: Hypothesizing that non-significant cerebrovascular lesions on structural brain imaging lead to overdiagnosis of a vascular etiology of dementia as compared to autopsy-confirmed diagnosis, we set up a study including 71 patients with autopsy-confirmed diagnoses. Forty-two patients in the population (59%) appeared to have definite Alzheimer's disease (AD), whereas 29 (41%) had a non-AD dementia form. The panel clinically diagnosed possible or probable vascular dementia (VaD) in 27 (38%) patients, whereas only five (19%) patients (p = 0.017) had an autopsy-confirmed diagnosis of VaD. Patients with vascular lesions on structural brain imaging were often misdiagnosed as possible or probable VaD as …compared to autopsy-confirmed diagnosis. Show more

Keywords: Alzheimer's disease, brain imaging, dementia, differential dementia diagnosis, magnetic resonance imaging, vascular dementia

DOI: 10.3233/JAD-142103

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1039-1043, 2015

Authors: Roubaud Baudron, Claire | Chambonnier, Lucie | Buissionnière, Alice | Giese, Alban | Macrez, Nathalie | Cho, Yoon | Fénelon, Valérie | Blaszczyk, Lucie | Dubus, Pierre | Lehours, Philippe | Mégraud, Francis | Salles, Nathalie | Varon, Christine

Article Type: Short Communication

Abstract: There is increasing evidence to support the role of infectious agents in the progression of Alzheimer's disease (AD), especially Helicobacter pylori (H. pylori). The impact of Helicobacter infection on the brain of non-AD predisposed mice was studied. For that, C57BL/6J mice were infected by oral gavage with H. pylori SS1 (n = 6) and Helicobacter felis (H. felis) (n = 6) or not infected (n = 6) for evaluation of neuroinflammation (anti-GFAP and anti-iba1 immunohistochemistry) and amyloid-β deposition (thioflavin-S stain and anti-Aβ immunohistochemistry). After 18-month of infection, H. pylori SS1 and H. felis infection induced a strong gastric inflammation compared …to non-infected mice, but did not induce brain neuroinflammation or amyloid-β deposition. Show more

Keywords: Alzheimer's disease, dementia, GFAP, Helicobacter pylori, iba 1, neuroinflammation, thioflavin-S

DOI: 10.3233/JAD-143129

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1045-1050, 2015

Authors: Rice, Ann C. | Ladd, Amy C. | Bennett Jr, James P.

Article Type: Research Article

Abstract: Causes of initiation and progression of sporadic Alzheimer's disease (sAD) are likely multiple and include impairment of mitochondrial bioenergetics. We analyzed RNA expression levels of multiple mitochondrial oxidative phosphorylation (OXPHOS) and biogenesis (mitobiogenesis) genes in unfixed hippocampal (WH) frozen sections (10 sAD; 9 CTL) and laser-captured hippocampal pyramidal neurons (PyNs, ~1000 neurons from each case) from 8 sAD and 7 CTL cases. Nuclear-encoded OXPHOS genes in WH were significantly increased in sAD, whereas in isolated sAD PyNs, these same genes were significantly decreased. Mitochondrial DNA-encoded genes were increased in sAD PyNs but showed a non-significant downward trend in sAD WH. …Relationships among WH and PyN gene expression levels in sAD distributed in a different population compared to CTL. Principal component analysis (PCA) revealed clustering of CTL but widespread heterogeneity of sAD samples. In sAD, mitochondrial bioenergetics at the gene expression level are depressed in vulnerable PyNs. PCA revealed that CTL samples clustered together, whereas sAD samples varied widely. From the perspective of OXPHOS bioenergetics, sAD is a heterogeneous syndrome and not likely due to a single abnormality. Increased stimulation of nuclear-encoded OXPHOS gene expression in PyNs is a rational therapeutic approach for most but not all cases of sAD. Show more

Keywords: Laser capture microdissection, mitochondria, mitochondrial biogenesis, relative gene expression, quantitative PCR

DOI: 10.3233/JAD-142937

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1051-1059, 2015

Authors: Sun, Ying | Bresell, Anders | Rantalainen, Mattias | Höglund, Kina | Lebouvier, Thibaud | Salter, Hugh | the Alzheimer Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common form of dementia, with no disease-modifying treatment yet available. Early detection of patients at risk of developing AD is of central importance. Blood-based genetic signatures can serve as early detection and as population-based screening tools. In this study, we aimed to identify genetic markers and gene signatures associated with cerebrospinal fluid (CSF) biomarkers levels of t-tau, p-tau181 , and with the two ratios t-tau/Aβ1-42 and p-tau181 /Aβ1-42 in the context of progression from mild cognitive impairment (MCI) to AD, and to identify a panel of genetic markers that can predict CSF …biomarker p-tau181 /Aβ1-42 ratio with consideration of APOE ε4 stratification. We analyzed genome-wide the Alzheimer's Disease Neuroimaging Initiative dataset with up to 48 months follow-up. In the first part of the analysis, the main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed for each of the four CSF biomarkers. In the second part of the analysis, we performed an integrated analysis of genome-wide association study results with pathway enrichment analysis, predictive modeling and network analysis in the subgroup of ApoE4-negative subjects. We identified a panel of five SNPs, rs6766238, rs1143960, rs1249963, rs11975968, and rs4836493, that are predictive for p-tau181 /Aβ1-42 ratio (high/low) with a sensitivity of 66% and a specificity of 70% (AUC 0.74). These results suggest that a panel of SNPs is a potential prognostic biomarker in ApoE4-negative MCI patients. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, genome-wide association study, mild cognitive impairment, multivariate analysis, pathway analysis, predictive model

DOI: 10.3233/JAD-142118

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1061-1076, 2015

Authors: Leuzy, Antoine | Carter, Stephen F. | Chiotis, Konstantinos | Almkvist, Ove | Wall, Anders | Nordberg, Agneta

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) pathology can be quantified in vivo using cerebrospinal fluid (CSF) levels of amyloid-β1-42 (Aβ1-42 ), total-tau (t-tau), and phosphorylated tau (p-tau181p ), as well as with positron emission tomography (PET) using [11 C]Pittsburgh compound-B ([11 C]PIB). Studies assessing concordance between these measures, however, have provided conflicting results. Moreover, it has been proposed that [11 C]PIB PET may be of greater clinical utility in terms of identifying patients with mild cognitive impairment (MCI) who will progress to the dementia phase of AD. Objective: To determine concordance and classification accuracy of CSF biomarkers and [11 …C]PIB PET in a cohort of patients with MCI and AD. Methods: 68 patients (MCI, n = 33; AD, n = 35) underwent [11 C]PIB PET and CSF sampling. Cutoffs of >1.41 ([11 C]PIB), <450 pg/mL—and a more lenient cutoff of 550 pg/mL—(Aβ1-42 ), <6.5 (Aβ1-42 /p-tau181p ), and 1.14 (Aβ1-42 /t-tau), were used to determine concordance. Logistic regression was used to determine classification accuracy with respect to stable MCI (sMCI) versus MCI who progressed to AD (pMCI). Results: Concordance between [11 C]PIB and Aβ1-42 was highest for sMCI (67%), followed by AD (60%) and pMCI (33%). Agreement was increased across groups using Aβ1-42 <550 pg/mL, or Aβ1-42 to tau ratios. Logistic regression showed that classification accuracy of [11 C]PIB, between sMCI and pMCI, was superior to Aβ1-42 (73% versus 58%), Aβ1-42 /t-tau (63%), and Aβ1-42 /p-tau181p (65%). Conclusion: In the present study, [11 C]PIB proved a better predictor of progression to AD in patients with MCI, relative to CSF measures of Aβ1-42 or Aβ1-42 /tau. Discordance between PET and CSF markers for Aβ1-42 suggests they cannot be used interchangeably, as is currently the case. Show more

Keywords: [11C]PIB, Alzheimer's disease, amyloid, cerebrospinal fluid, mild cognitive impairment, positron emission tomography, tau

DOI: 10.3233/JAD-142952

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1077-1088, 2015

Authors: Moon, Yeonsil | Moon, Won-Jin | Kwon, Hunki | Lee, Jong-Min | Han, Seol-Heui

Article Type: Research Article

Abstract: Background: Emerging evidence suggests that low serum 25-hydroxyvitamin D (25OHD) may induce cognitive decline and dementia, however, the pathophysiological mechanisms are poorly understood. Objective: We sought to determine the relationship between vitamin D deficiency and neuronal integrity in cognitively impaired patients. Methods: One hundred nine patients with memory impairment were divided into quartiles according to serum concentrations of 25OHD concentration, from lowest (L-25OHD) to highest (H-25OHD). The diffusion tensor images from the L-25OHD group and the H-25OHD group were assessed. A mask of regional white matter hyperintensities was obtained in the T1-weighted image space. Data were …analyzed using tract-based spatial statistics with a nonlinear registration algorithm. Results: Patients in the L-25OHD group had lower fractional anisotropy values compared with patients in the H-25OHD group in the frontal parts of the inferior and superior longitudinal fasciculi, cingulum bundle, corpus callosum (genu), anterior limb of the internal capsule, and anterior corona radiata (familywise error corrected, p < 0.05). Conclusions: Vitamin D deficiency is associated with disruption of neuronal integrity, primarily in frontal regions. Vitamin D deficiency may lead to the loss of neuroprotective properties in cerebral ischemia and vascular lesions, contributing to memory impairment. Show more

Keywords: Cognitive decline, imaging, nutritional, vitamin D

DOI: 10.3233/JAD-143063

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1089-1096, 2015

Authors: Di Paola, Margherita | Phillips, Owen | Orfei, Maria Donata | Piras, Fabrizio | Cacciari, Claudia | Caltagirone, Carlo | Spalletta, Gianfranco

Article Type: Research Article

Abstract: Corpus callosum (CC) abnormalities may cause cognitive and neuropsychiatric complications due to reduced hemispheric integration. Over a one-year period, we investigated whether the CC structure of 20 patients with mild Alzheimer's disease (AD) was linked to the evolution of cognitive and neuropsychiatric symptoms. We also investigated whether this anatomical-clinical relationship was localized topographically on the CC by combining voxel-based morphometry and diffusion tensor imaging approaches. We assessed patients' global cognitive deterioration and neuropsychiatric symptoms with the Mini-Mental State Examination and the Neuropsychiatric Inventory. Increased global cognitive deterioration during the early course of AD was significantly related to reduced white matter …density (p = 0.004) and fractional anisotropy (FA) (p = 0.012) and increased mean diffusivity (MD) (p = 0.017) at the level of the CC isthmus/splenium. Further, increased depression severity was significantly related to reduced FA (p = 0.008) and increased MD (p = 0.018) at the level of the CC rostrum. These results indicate that changes in early myelinated CC fibers, which subserve the lateral temporal and parietal cortices and are less vulnerable to damage, may be related to cognitive impairment. Furthermore, changes in late myelinated CC fibers, which connect the orbitofrontal cortices and are more vulnerable to damage, may be related to the earliest neuropsychiatric symptoms of AD, such as depression. Show more

Keywords: Cognitive domain, corpus callosum, depression, diffusion tensor imaging , diffusivity, drug-free, first diagnosed AD, fractional anisotropy, mean diffusivity, mild Alzheimer's disease, Mini-Mental State Examination, neuropsychiatric symptoms, structural MRI, volume, voxel-based morphometry

DOI: 10.3233/JAD-142895

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1097-1108, 2015