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

Authors: Whitwell, Jennifer L. | Kantarci, Kejal | Weigand, Stephen D. | Lundt, Emily S. | Gunter, Jeffrey L. | Duffy, Joseph R. | Strand, Edythe A. | Machulda, Mary M. | Spychalla, Anthony J. | Drubach, Daniel A. | Petersen, Ronald C. | Lowe, Val J. | Jack Jr., Clifford R. | Josephs, Keith A.

Article Type: Research Article

Abstract: Background: Microbleeds in the brain have been shown to occur in Alzheimer’s disease (AD), affecting approximately a third of subjects that present with typical dementia of the Alzheimer’s type (DAT). However, little is known about the frequency or distribution of microbleeds in subjects with AD that present with atypical clinical presentations. Objective: To determine whether the frequency and regional distribution of microbleeds in atypical AD differs from that observed in subjects with DAT, and to determine whether microbleeds in atypical AD are associated with age, demographics, or cognitive impairment. Methods: Fifty-five subjects with amyloid-β deposition on …Pittsburgh compound B (PiB) PET who presented with predominant language (n = 37) or visuospatial/perceptual (n = 18) deficits underwent T2*weighted MRI. These subjects were compared to 41 PiB-positive subjects with DAT. Microbleeds were identified and assigned a lobar location. Results: The proportion of subjects with microbleeds did not differ between atypical AD (42%) and DAT (32%). However, atypical AD had larger numbers of microbleeds than DAT. In addition, the topographic distribution of microbleeds differed between atypical AD and DAT, with atypical AD showing the highest density of microbleeds in the frontal lobes. Among atypical AD, number of microbleeds was associated with age, but not gender or cognition. Microbleeds were more common in subjects with language (51%) versus visuospatial/perceptual deficits (22%). Conclusions: Microbleeds are relatively common in both DAT and atypical AD, although atypical AD subjects appear to be at particular risk for developing large numbers of microbleeds and for developing microbleeds in the frontal lobe. Show more

Keywords: Alzheimer's disease, amyloid-β, dementia of the Alzheimer's type, early-onset Alzheimer's disease, logopenic, magnetic resonance imaging, microbleeds, positron emission tomography, posterior cortical atrophy

DOI: 10.3233/JAD-142628

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1109-1117, 2015

Authors: Nagel, Gabriele | Herbolsheimer, Florian | Riepe, Matthias | Nikolaus, Thorsten | Denkinger, Michael D. | Peter, Richard | Weinmayr, Gudrun | Rothenbacher, Dietrich | Koenig, Wolfgang | Ludolph, Albert C. | von Arnim, Christine A.F. | the ActiFE Study group

Article Type: Research Article

Abstract: Our objective was to investigate the associations of vitamin D serum levels with dementia and cognitive function in specific domains in community dwelling older adults. Between 2009 and 2010, we conducted a cross-sectional study in 1,373 individuals (56% men) aged 65+ years in the “Activity and Function in the Elderly in Ulm” (ActiFE) study. Dementia was defined as a Mini-Mental State Examination (MMSE) score ≤ 24. The 25-OHD serum level [ng/mL] was measured by an electrochemilumineszenz immunoassay (ECLIA). Logistic regression models were used to calculate odds ratios (OR)s for cognitive domains (cut-point: 10th percentile) by serum 25-OHD concentrations (both continuously …and by cut-point of 20 ng/ml for vitamin D deficiency). Mean age of the study population was 75.6 (SD 6.6) years. We identified 75 participants (43% women) with dementia. 25-OHD concentrations were significantly lower in the participants with dementia compared to persons with a MMSE score >24. We also observed an association of continuous 25-OHD serum concentrations with prevalence of dementia (crude OR 1.05, 95% confidence interval (CI), 1.01–1.08, p-value 0.009) per 1 ng/mL decrease, after adjustment the OR was 1.03, 95% CI, 0.995–1.08 (p-value 0.09). Although vitamin D deficiency was tentatively associated with severity of dementia measured by MMSE (OR 1.35, 95% CI, 0.84–2.19), the association was not statistically significant. However, deficits in specific cognitive domains such as executive functions, wordlist encoding, and visual memory (encoding and recall) were significantly associated with low vitamin D concentration. Our results suggest an association between vitamin D deficiency and cognitive function in specific domains in community dwelling older adults. Show more

Keywords: Cognitive function, dementia, older population, vitamin D

DOI: 10.3233/JAD-143219

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1119-1126, 2015

Authors: Subramaniam, Mythily | Chong, Siow Ann | Vaingankar, Janhavi Ajit | Abdin, Edimansyah | Chua, Boon Yiang | Chua, Hong Choon | Eng, Goi Khia | Heng, Derrick | Hia, Soo Boon | Huang, Wanping | Jeyagurunathana, Anitha | Kua, Joshua | Lee, Siau Pheng | Mahendran, Rathi | Magadi, Harish | Malladi, Srinivasa | McCrone, Paul | Pang, Shirlene | Picco, Louisa | Sagayadevan, Vathsala | Sambasivam, Rajeswari | Seng, Kok Han | Seow, Esmond | Shafie, Saleha | Shahwan, Shazana | Tan, Lay Ling | Yap, Mabel | Zhang, YunJue | Ng, Li Ling | Prince, Martin

Article Type: Research Article

Abstract: Background: The challenge of an aging population with its expected attendant problem of an increase in the number of people with dementia is a growing concern across the world. Objective: The aims of this study were to establish the prevalence and risk factors of dementia in Singapore among the elderly resident population (aged 60 years and above). Methods: The WiSE study was a comprehensive single phase, cross-sectional, epidemiological survey that adapted the 10/66 protocol to establish the 10/66 and the Diagnostic and Statistical Manual of mental disorders –fourth edition (DSM-IV) diagnosis of dementia. 10/66 and DSM-IV …dementia diagnosis as established by the survey questionnaires was validated by comparing against a gold standard of clinical assessment. Results: A total of 2,565 respondents completed the study giving a response rate of 65.6%. The validity of 10/66 dementia was higher (sensitivity = 95.6%, specificity = 81.8%) than that of DSM-IV dementia (sensitivity = 75.6%, specificity = 88.6%) when compared against the clinical gold standard. The study found that the prevalence of 10/66 dementia was 10% in the older adult population while the prevalence of DSM-IV dementia was 4.6%. Older age (75 years and above); no formal education, or completed primary education (versus higher education); homemaker and retired status (versus employed); and a history of stroke were associated with a higher risk of 10/66 dementia. Conclusion: The establishment of accurate data on the number of people with dementia is essential in the planning of services and initiatives. Show more

Keywords: 10/66, dementia, DSM-IV, multi-ethnic, prevalence, Singapore

DOI: 10.3233/JAD-142769

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1127-1138, 2015

Authors: Sun, Shu-Wei | Nishioka, Christopher | Labib, Wessam | Liang, Hsiao-Fang

Article Type: Research Article

Abstract: Background: Synaptic deficits and neuronal loss are the major pathological manifestations of Alzheimer’s disease. However, the link between the early synaptic loss and subsequent neurodegeneration is not entirely clear. Cell culture studies have shown that amyloid-β (Aβ) applied to axonal terminals can cause retrograde degeneration leading to the neuronal loss, but this process has not been demonstrated in live animals. Objective: To test if Aβ applied to retinal ganglion cell axonal terminals can induce axonal damage in the optic nerve and optic tract in mice. Methods: Aβ was injected into the terminal field of the optic …tract, in the left lateral geniculate nucleus of wildtype C57BL/6 mice. Following the injection, monthly diffusion tensor imaging was performed. Three months after the injection, mice underwent visual evoked potential recordings, and then sacrificed for immunohistochemical examination. Results: There were no significant changes seen with diffusion tensor imaging in the optic nerve and optic tract 3 months after the Aβ injection. The myelin and axons in these regions remained intact according to immunohistochemistry. The only significant changes observed in this study were delayed transduction and reduced amplitude of visual evoked potentials, although both Aβ and its reversed form caused similar changes. Conclusion: Despite the published in vitro studies, there was no significant axonal damage in the optic nerve and optic tract after injecting Aβ onto retinal ganglion cell axonal terminals of wildtype C57BL/6 mice. Show more

Keywords: Amyloid-β injection, diffusion tensor image, mouse, retinal ganglion cell, retrograde degeneration, visual evoked potential

DOI: 10.3233/JAD-142154

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1139-1148, 2015

Authors: Darst, Burcu F. | Koscik, Rebecca L. | Hermann, Bruce P. | La Rue, Asenath | Sager, Mark A. | Johnson, Sterling C. | Engelman, Corinne D.

Article Type: Research Article

Abstract: Cognitive decline is one of the hallmark features of Alzheimer's disease, but many studies struggle to find strong associations between cognitive function and genetic variants. In order to identify which aspects of cognition are more likely to have a strong genetic component, we assessed the heritability of various cognitive functions related to Alzheimer's disease in 303 initially asymptomatic middle-aged adult siblings with a parental history of Alzheimer's disease from the Wisconsin Registry for Alzheimer's Prevention. Participants underwent extensive cognitive testing, and six cognitive factors were identified via factor analysis. Working Memory and Visual Learning & Memory had the highest heritability …(52% and 41%, respectively). Inclusion of APOE allele counts did not notably change heritability estimates, indicating that there are likely additional genetic variants contributing to cognition. These findings suggest that future genetic studies should focus on the cognitive domains of Working Memory and Visual Learning & Memory. Show more

Keywords: Alzheimer's disease, APOE, cognitive function, genetics, heritability, WRAP

DOI: 10.3233/JAD-142658

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1149-1155, 2015

Authors: Olazarán, Javier | Gil-de-Gómez, Luis | Rodríguez-Martín, Andrés | Valentí-Soler, Meritxell | Frades-Payo, Belén | Marín-Muñoz, Juan | Antúnez, Carmen | Frank-García, Ana | Acedo-Jiménez, Carmen | Morlán-Gracia, Lorenzo | Petidier-Torregrossa, Roberto | Guisasola, María Concepción | Bermejo-Pareja, Félix | Sánchez-Ferro, Álvaro | Pérez-Martínez, David A. | Manzano-Palomo, Sagrario | Farquhar, Ruth | Rábano, Alberto | Calero, Miguel

Article Type: Research Article

Abstract: Accurate blood-based biomarkers of Alzheimer's disease (AD) could constitute simple, inexpensive, and non-invasive tools for the early diagnosis and treatment of this devastating neurodegenerative disease. We sought to develop a robust AD biomarker panel by identifying alterations in plasma metabolites that persist throughout the continuum of AD pathophysiology. Using a multicenter, cross-sectional study design, we based our analysis on metabolites whose levels were altered both in AD patients and in patients with amnestic mild cognitive impairment (aMCI), the earliest identifiable stage of AD. UPLC coupled to mass spectrometry was used to independently compare the levels of 495 plasma metabolites in …aMCI (n = 58) and AD (n = 100) patients with those of normal cognition controls (NC, n = 93). Metabolite alterations common to both aMCI and AD patients were used to generate a logistic regression model that accurately distinguished AD from NC patients. The final panel consisted of seven metabolites: three amino acids (glutamic acid, alanine, and aspartic acid), one non-esterified fatty acid (22:6n-3, DHA), one bile acid (deoxycholic acid), one phosphatidylethanolamine [PE(36:4)], and one sphingomyelin [SM(39:1)]. Detailed analysis ruled out the influence of potential confounding variables, including comorbidities and treatments, on each of the seven biomarkers. The final model accurately distinguished AD from NC patients (AUC, 0.918). Importantly, the model also distinguished aMCI from NC patients (AUC, 0.826), indicating its potential diagnostic utility in early disease stages. These findings describe a sensitive biomarker panel that may facilitate the specific detection of early-stage AD through the analysis of plasma samples. Show more

Keywords: Alzheimer's disease, biomarkers, diagnosis, mild cognitive impairment, plasma

DOI: 10.3233/JAD-142925

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1157-1173, 2015

Authors: Campbell, Shannon N. | Zhang, Cheng | Roe, Allyson D. | Lee, Nickey | Lao, Kathleen U. | Monte, Louise | Donohue, Michael C. | Rissman, Robert A.

Article Type: Research Article

Abstract: Stress exposure and the corticotropin-releasing factor (CRF) system have been implicated as mechanistically involved in both Alzheimer's disease (AD) and associated rodent models. In particular, the major stress receptor, CRF receptor type 1 (CRFR1), modulates cellular activity in many AD-relevant brain areas, and has been demonstrated to impact both tau phosphorylation and amyloid-β (Aβ) pathways. The overarching goal of our laboratory is to develop and characterize agents that impact the CRF signaling system as disease-modifying treatments for AD. In the present study, we developed a novel transgenic mouse to determine whether partial or complete ablation of CRFR1 was feasible in …an AD transgenic model and whether this type of treatment could impact Aβ pathology. Double transgenic AD mice (PSAPP) were crossed to mice null for CRFR1; resultant CRFR1 heterozygous (PSAPP-R1+/− ) and homozygous (PSAPP-R1−/− ) female offspring were used at 12 months of age to examine the impact of CRFR1 disruption on the severity of AD Aβ levels and pathology. We found that both PSAPP-R1+/− and PSAPP-R1−/− had significantly reduced Aβ burden in the hippocampus, insular, rhinal, and retrosplenial cortices. Accordingly, we observed dramatic reductions in Aβ peptides and AβPP-CTFs, providing support for a direct relationship between CRFR1 and Aβ production pathways. In summary, our results suggest that interference of CRFR1 in an AD model is tolerable and is efficacious in impacting Aβ neuropathology. Show more

Keywords: Alzheimer's disease, amyloid-β, corticotropin-releasing factor, corticotropin-releasing factor receptor 1, hippocampus, hypothalamic-pituitary adrenal axis, stress, triple transgenic

DOI: 10.3233/JAD-142844

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1175-1184, 2015

Authors: Wang, Ying | Wang, Ying | Sui, Yi | Yu, Hongshuang | Shen, Xiaoheng | Chen, Shengdi | Pei, Gang | Zhao, Jian | Ding, Jianqing

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a common neurodegenerative disease affecting cognitive function in the elderly, which is characterized by the presence of extracellular deposits of insoluble amyloid-β plaques and neuronal loss. Modern pharmacology and drug development usually follow a single-target principle, which might contribute to the failure of most compounds in clinical trials against AD. Considering AD is a multifactorial disease, a combination therapeutic strategy that applies drugs with different mechanisms would be an alternative way. Smart Soup (SS), a Traditional Chinese Medicine formula, is composed of three herbaceous plants and has been applied in the treatment of amnesia in China …for hundreds of years. In this work, we studied the clinical potency of the combination of SS and Aricept in AD therapy. In the in vivo model, both longevity and locomotive activity of AD transgenic Drosophila were improved remarkably in the combined medicine treated group. We also observed less amyloid-β deposition and retarded neuronal loss following the combined drug treatment. In the retrospective cohort study, we found the combination therapy exerted better therapeutic effect on AD patients. Our study revealed that combination therapy with multiple drug targets did have a better therapeutic outcome. It provides a new strategy to develop an optimum pharmaceutical approach against AD. Show more

Keywords: Alzheimer's disease, Traditional Chinese Medicine, Smart Soup (SS), Aricept, combination therapy

DOI: 10.3233/JAD-143183

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1185-1195, 2015

Authors: Nho, Kwangsik | Ramanan, Vijay K. | Horgusluoglu, Emrin | Kim, Sungeun | Inlow, Mark H. | Risacher, Shannon L. | McDonald, Brenna C. | Farlow, Martin R. | Foroud, Tatiana M. | Gao, Sujuan | Callahan, Christopher M. | Hendrie, Hugh C. | Niculescu, Alexander B. | Saykin, Andrew J. | for the Alzheimer's Disease Neuroimaging Initiative (ADNI)

Article Type: Research Article

Abstract: Depressive symptoms are common in older adults and are particularly prevalent in those with or at elevated risk for dementia. Although the heritability of depression is estimated to be substantial, single nucleotide polymorphism-based genome-wide association studies of depressive symptoms have had limited success. In this study, we performed genome-wide gene- and pathway-based analyses of depressive symptom burden. Study participants included non-Hispanic Caucasian subjects (n = 6,884) from three independent cohorts, the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Health and Retirement Study (HRS), and the Indiana Memory and Aging Study (IMAS). Gene-based meta-analysis identified genome-wide significant associations (ANGPT4 and FAM110A, q-value …= 0.026; GRM7-AS3 and LRFN5, q-value = 0.042). Pathway analysis revealed enrichment of association in 105 pathways, including multiple pathways related to ERK/MAPK signaling, GSK3 signaling in bipolar disorder, cell development, and immune activation and inflammation. GRM7, ANGPT4, and LRFN5 have been previously implicated in psychiatric disorders, including the GRM7 region displaying association with major depressive disorder. The ERK/MAPK signaling pathway is a known target of antidepressant drugs and has important roles in neuronal plasticity, and GSK3 signaling has been previously implicated in Alzheimer's disease and as a promising therapeutic target for depression. Our results warrant further investigation in independent and larger cohorts and add to the growing understanding of the genetics and pathobiology of depressive symptoms in aging and neurodegenerative disorders. In particular, the genes and pathways demonstrating association with depressive symptoms may be potential therapeutic targets for these symptoms in older adults. Show more

Keywords: ANGPT4, depressive symptoms, genome-wide association study, GRM7, GSK3, MAPK-ERK

DOI: 10.3233/JAD-148009

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1197-1206, 2015

Authors: Lee, Dahee | Kim, Won Chul | Charidimou, Andreas | Song, Min

Article Type: Research Article

Abstract: During the last 30 years, Alzheimer's disease (AD) research, aiming to understand the pathophysiology and to improve the diagnosis, management, and, ultimately, treatment of the disease, has grown rapidly. Recently, some studies have used simple bibliometric approaches to investigate research trends and advances in the field. In our study, we map the AD research field by applying entitymetrics, an extended concept of bibliometrics, to capture viewpoints of indexers, authors, or citers. Using the full-text documents with reference section retrieved from PubMed Central, we constructed four types of networks: MeSH-MeSH (MM), MeSH-Citation-MeSH (MCM), Keyphrase-Keyphrase (KK), and Keyphrase-Citation-Keyphrase (KCK) networks. The working …hypothesis was that MeSH, keyphrase, and citation relationships reflect the views of indexers, authors, and/or citers, respectively. In comparative network and centrality analysis, we found that those views are different: indexers emphasize amyloid-related entities, including methodological terms, while authors focus on specific biomedical terms, including clinical syndromes. The more dense and complex networks of citing relationships reported in our study, to a certain extent reflect the impact of basic science discoveries in AD. However, none of these could have had clinical relevance for patients without close collaboration between investigators in translational and clinical-related AD research (reflected in indexers and authors' networks). Our approach has relevance for researches in the field, since they can identify relations between different developments which are not otherwise evident. These developments combined with advanced visualization techniques, might aid the discovery of novel interactions between genes and pathways or used as a resource to advance clinical drug development. Show more

Keywords: Alzheimer's disease, bibliometrics, literature based discovery, medical informatics, Parkinson's disease

DOI: 10.3233/JAD-142688

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1207-1222, 2015

Authors: Richard, Bernhard Clemens | Kurdakova, Anastasiia | Baches, Sandra | Bayer, Thomas A. | Weggen, Sascha | Wirths, Oliver

Article Type: Research Article

Abstract: In the present report, we extend previous findings in the 5XFAD mouse model with regard to a characterization of behavioral deficits and neuropathological alterations. We demonstrate that these mice develop a robust age-dependent motor phenotype and spatial reference memory deficits when bred to homozygosity, leading to a strongly reduced age of onset of behavioral symptoms. At postnatal day sixteen, abundant AβPP was detected in subiculum and cortical pyramidal neurons. From six weeks on, intraneuronal Aβ could be detected which was much more abundant in homozygous mice. The same gene-dosage effect was seen on memory and motor deficits. While at 2 …months of age neither heterozygous nor homozygous 5XFAD mice show any neurological phenotype except for alterations in anxiety behavior, at 5 months they were clearly evident. Interestingly, despite abundant motor deficiencies, homozygous 5XFAD mice were able to perform the acquisition training of the Morris water maze task with no difference in the swimming performance between the groups. Therefore the aggravated spatial memory and spatial reference memory deficits of the homozygous mice correlated with the elevated soluble and insoluble Aβ levels. Homozygous 5XFAD mice represent a model with several advantages in comparison to the heterozygous mice, developing amyloid pathology much more rapidly together with a neurological phenotype. These advantages allow reducing the number of animals for Alzheimer's disease research. Show more

Keywords: Amyloid, axonal degeneration, behavior, intraneuronal Aβ, motor deficit, spatial memory, transgenic mice, 5XFAD

DOI: 10.3233/JAD-143120

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1223-1236, 2015

Authors: Vassilaki, Maria | Cha, Ruth H. | Aakre, Jeremiah A. | Therneau, Terry M. | Geda, Yonas E. | Mielke, Michelle M. | Knopman, David S. | Petersen, Ronald C. | Roberts, Rosebud O.

Article Type: Research Article

Abstract: Background: Etiologic differences in mild cognitive impairment (MCI) subtypes may impact mortality. Objective: To assess the rate of death in MCI overall, and by subtype, in the population-based Mayo Clinic Study of Aging. Methods: Participants aged 70–89 years at enrollment were clinically evaluated at baseline and 15-month intervals to assess diagnoses of MCI and dementia. Mortality in MCI cases versus cognitively normal (CN) individuals was estimated using Cox proportional hazards models. Results: Over a median follow-up of 5.8 years, 331 of 862 (38.4%) MCI cases and 224 of 1,292 (17.3%) cognitively normal participants died. …Compared to CN individuals, mortality was elevated in persons with MCI (hazard ratio [HR] = 2.03; 95% CI: 1.61 to 2.55), and was higher for non-amnestic MCI (naMCI; HR = 2.47; 95% CI: 1.80 to 3.39) than for amnestic MCI (aMCI; HR = 1.89; 95% CI: 1.48 to 2.41) after adjusting for confounders. Mortality varied significantly by sex, education, history of heart disease, and engaging in moderate physical exercise (p for interaction <0.05 for all). Mortality rate estimates were highest in MCI cases who were men, did not exercise, had heart disease, and had higher education versus CN without these factors, and for naMCI cases versus aMCI cases without these factors. Conclusions: These findings suggest stronger impact of etiologic factors on naMCI mortality. Prevention of heart disease, exercise vigilance, may reduce MCI mortality and delayed MCI diagnosis in persons with higher education impacts mortality. Show more

Keywords: Cohort studies, incidence studies, mild cognitive impairment, mortality, outcomes research, prognosis

DOI: 10.3233/JAD-143078

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1237-1245, 2015

Authors: Wisse, Laura E.M. | Reijmer, Yael D. | ter Telgte, Annemieke | Kuijf, Hugo J. | Leemans, Alexander | Luijten, Peter R. | Koek, Huiberdina L. | Geerlings, Mirjam I. | Biessels, Geert Jan | on behalf of the Utrecht Vascular Cognitive Impairment (VCI) Study Group

Article Type: Research Article

Abstract: Background: In patients with Alzheimer’s disease (AD), atrophy of the entorhinal cortex (ERC) and hippocampal formation may induce degeneration of connecting white matter tracts. Objective: We examined the association of hippocampal subfield and ERC atrophy at 7 tesla MRI with fornix and parahippocampal cingulum (PHC) microstructure in patients with early AD. Methods: Twenty-five patients with amnestic mild cognitive impairment (aMCI) (n = 15) or early AD (n = 10) and 17 controls underwent 3 tesla diffusion MRI to obtain fractional anisotropy (FA) of the fornix and PHC and 7 tesla MRI to obtain ERC and hippocampal …subfield volumes. Linear regression analyses were performed, adjusted for age, gender, and intracranial volume. Results: Fornix FA was significantly lower and subiculum, cornu ammonis (CA) 1, and dentate gyrus &CA4 volume were significantly smaller in patients with MCI or AD as compared to controls. In patients with MCI or AD, fornix FA was positively associated with subiculum volume (β = 0.53, 95% CI 0.10; 0.96), but not with ERC/other subfield volumes. PHC FA was not associated with ERC/subfield volumes. Conclusion: These findings indicate that in early AD subiculum atrophy is associated with lower FA of the fornix, which primarily consists of axons originating in the subiculum. This suggests that degeneration of subicular cell bodies and their axons are related processes in early AD. Show more

Keywords: Alzheimer's disease, diffusion magnetic resonance imaging, fornix, hippocampus, mild cognitive impairment, subiculum

DOI: 10.3233/JAD-142994

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1247-1256, 2015

Authors: Kowoll, Magdalena Eva | Degen, Christina | Gladis, Saskia | Schröder, Johannes

Article Type: Research Article

Abstract: Bilingualism is associated with enhanced executive functioning and delayed onset of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Here, we investigated neuropsychological differences between mono- and bilingual patients with MCI and AD as well as the respective effects of dementia on the dominant and non-dominant language of bilinguals. 69 patients with MCI (n = 22) or AD (n = 47) and 17 healthy controls were included. 41 subjects were classified as lifelong bilinguals (mean age: 73.6; SD = 11.5) and 45 as monolinguals (mean age: 78.1; SD = 10.9). Neuropsychological performance was assessed on the CERAD-NP, the clock-drawing …test, and the logical memory subscale of the Wechsler Memory Scale. Neuropsychological profiles showed only minor nonsignificant differences between mono- and bilingual subjects when compared between diagnostic groups. Bilingual MCI patients scored significantly lower on the verbal fluency and picture naming task in their dominant language than bilingual controls. Bilingual AD patients showed a reduced performance in their nondominant language when compared to bilingual MCI patients and bilingual controls (main effect language dominance: verbal fluency task p < 0.001; BNT p < 0.001). Bilingual MCI and AD patients show a similar pattern of neuropsychological deficits as monolingual patients do. The dominant language appears to be compromised first in bilingual MCI patients, while severe deficits of the nondominant language develop later in the course with manifestation of AD. These findings are important for the diagnostic work up of bilingual patients and the development of improved care concepts for bilingual patients such as migrant populations. Show more

Keywords: Alzheimer's disease, bilingualism, mild cognitive impairment, picture naming, verbal fluency

DOI: 10.3233/JAD-142880

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1257-1268, 2015

Article Type: Correction

DOI: 10.3233/JAD-159002

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1269-1270, 2015

Article Type: Other

DOI: 10.3233/JAD-150005

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1271-1273, 2015

Article Type: Other

DOI: 10.3233/JAD-2015-45427

Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1275-1287, 2015