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

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