Journal of Alzheimer's Disease - Volume 40, issue 1

Authors: Perez, Felipe P. | Bose, David | Maloney, Bryan | Nho, Kwangsik | Shah, Kavita | Lahiri, Debomoy K.

Article Type: Review Article

Abstract: Late-onset Alzheimer's disease (LOAD) is the most common neurodegenerative disorder in older adults, affecting over 50% of those over age 85. Aging is the most important risk factor for the development of LOAD. Aging is associated with the decrease in the ability of cells to cope with cellular stress, especially protein aggregation. Here we describe how the process of aging affects pathways that control the processing and degradation of abnormal proteins including amyloid-β (Aβ). Genetic association studies in LOAD have successfully identified a large number of genetic variants involved in the development of the disease. However, there is a gap …in understanding the interconnections between these pathomolecular events that prevent us from discovering therapeutic targets. We propose novel, pertinent links to elucidate how the biology of aging affects the sequence of events in the development of LOAD. Furthermore we analyze and synthesize the molecular-pathologic-clinical correlations of the aging process, involving the HSF1 and FOXO family pathways, Aβ metabolic pathway, and the different clinical stages of LOAD. Our new model postulates that the aging process would precede Aβ accumulation, and attenuation of HSF1 is an “upstream” event in the cascade that results in excess Aβ and synaptic dysfunction, which may lead to cognitive impairment and/or trigger “downstream” neurodegeneration and synaptic loss. Specific host factors, such as the activity of FOXO family pathways, would mediate the response to Aβ toxicity and the pace of progression toward the clinical manifestations of AD. Show more

Keywords: Amyloid, autophagy, cognition, dementia, heat-shock, neurodegeneration, protein aggregation, protein degradation, stress, transcription factor

DOI: 10.3233/JAD-131544

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 1-17, 2014

Authors: Maltsev, Alexander V. | Santockyte, Rasa | Bystryak, Simon | Galzitskaya, Oxana V.

Article Type: Research Article

Abstract: We present a new model for etiology of Alzheimer's disease (AD) which postulates early involvement of specialized neuroprotective mechanisms in the pathology of AD. These neuroprotective mechanisms work in concert to regulate metabolic homeostasis in healthy neuronal cells, but contribute to the distinctive cytopathic phenotype of neuronal degeneration in AD. According to this model, two molecular/genetic hallmarks of AD, amyloid-β (Aβ) deposition and tau hyperphosphorylation, are associated with neuronal mechanisms for dissipating thermal energy associated with high levels of protein synthesis in highly temperature-sensitive neuronal cells. Development of effective methods of AD treatment will require a better understanding of how …this neuronal defense system is activated in response to cytopathological triggers in sporadic AD. The cause and effect link between synthesis and processing of amyloid-β protein precursor (AβPP) and the AD terminal phenotype of neurofibrillary tangles and neuron loss involve the formation of Aβ peptides that accumulate as oligomers, cannot be controlled by neurons, and are toxic to the surrounding neuronal membranes. We analyze experimental and clinical studies that have investigated the correlation between phosphorylation of some transport proteins and increased synthesis of proteins in neurons. We also review the evidence related to the possibility that protein hyperphosphorylation may be a byproduct of energetic imbalances in AD cells associated with high levels of protein synthesis, and that activation of defense systems, through which energy-rich molecules are eliminated from the site of protein synthesis and are sequestered to the peripheral neuronal areas, may bring about some of the distinctive morphological features of AD. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, amyloidosis, cellular defense factors, hyperphosphorylation, neuron loss, phosphorylation, tau protein

DOI: 10.3233/JAD-131562

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 19-32, 2014

Authors: Flanagan, Emma C. | Tu, Sicong | Ahmed, Samrah | Hodges, John R. | Hornberger, Michael

Article Type: Short Communication

Abstract: Memory and orientation were investigated as predictors of underlying Alzheimer's disease (AD) pathology in patients with logopenic (lv) and non-fluent (na) variants of primary progressive aphasia (PPA). Memory and orientation scores from Addenbrooke's Cognitive Examination were compared between 26 lv-PPA, 29 na-PPA, 59 AD, and 90 controls using analysis of variance. Forty-five patients underwent Pittsburgh compound B (PiB) positron emission tomography scans. Patients with lv-PPA performed poorer on memory and orientation than na-PPA and did not differ from the AD group. Post-hoc analysis on the PiB-scanned subgroup corroborated these results. Memory and orientation profiles may supplement language assessment in identifying …patients with AD pathology. Show more

Keywords: Memory, orientation, PiB, PPA, lv-PPA, na-PPA

DOI: 10.3233/JAD-131448

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 33-36, 2014

Authors: Khan, Wasim | Giampietro, Vincent | Ginestet, Cedric | Dell'Acqua, Flavio | Bouls, David | Newhouse, Steven | Dobson, Richard | Banaschewski, Tobias | Barker, Gareth J. | Bokde, Arun L.W. | Büchel, Christian | Conrod, Patricia | Flor, Herta | Frouin, Vincent | Garavan, Hugh | Gowland, Penny | Heinz, Anreas | Ittermann, Bernd | Lemaître, Hervé | Nees, Frauke | Paus, Tomas | Pausova, Zdenka | Rietschel, Marcella | Smolka, Michael N. | Ströhle, Andreas | Gallinat, Jean | Westman, Eric | Schumann, Gunther | Lovestone, Simon | Simmons, Andrew | the IMAGEN consortium ()

Article Type: Short Communication

Abstract: Alleles of the apolipoprotein E (ApoE) gene are known to modulate the genetic risk for developing late-onset Alzheimer's disease (AD) and have been associated with hippocampal volume differences in AD. However, the effect of these alleles on hippocampal volume in younger subjects has yet to be clearly established. Using a large cohort of more than 1,400 adolescents, this study found no hippocampal volume or hippocampal asymmetry differences between carriers and non-carriers of the ApoE ε4 or ε2 alleles, nor dose-dependent effects of either allele, suggesting that regionally specific effects of these polymorphisms may only become apparent in later life.

Keywords: Apolipoprotein E, hippocampal volume, magnetic resonance imaging, young healthy adolescents

DOI: 10.3233/JAD-131841

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 37-43, 2014

Authors: Gussago, Cristina | Arosio, Beatrice | Casati, Martina | Ferri, Evelyn | Gualandris, Federica | Tedone, Enzo | Nicolini, Paola | Rossi, Paolo Dionigi | Abbate, Carlo | Mari, Daniela

Article Type: Short Communication

Abstract: The line between vascular dementia (VaD) and Alzheimer's disease (AD) is often blurred. In this study we investigated whether adenosine A2A receptor (A2A R) expression can be used to differentiate between VaD and AD. We evaluated the expression of this receptor in the peripheral blood mononuclear cells of patients with VaD, mild cognitive impairment, AD, and controls. We found statistically significant lower levels of A2A R mRNA in VaD compared to AD subjects. These data suggest that A2A R expression may help in the differential diagnosis between VaD and AD.

Keywords: Adenosine receptors, Alzheimer's disease, biomarker, vascular dementia

DOI: 10.3233/JAD-131652

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 45-49, 2014

Authors: Homma, Taku | Takubo, Hideki | Takahashi, Kazushi | Matsubara, Shiro | Takahashi, Manabu | Funata, Nobuaki | Mochizuki, Yoko | Mizutani, Toshio | Komori, Takashi | Uchihara, Toshiki

Article Type: Short Communication

Abstract: Corticobasal syndrome (CBS) is characterized by lateralized motor disturbance due to levodopa nonresponsive parkinsonism and progressive apraxia. Although CBS is neuropathologically heterogeneous, it remains unclear whether the clinical features of all CBS cases are the same. We report two autopsy cases diagnosed clinically as CBS and pathologically as Alzheimer's disease characterized by lateralized cerebral cortical degeneration and absence of significant nigrostriatial lesions. Cerebral cortical degeneration in both cases was contralateral to their motor disturbances. Thus, nigrostriatial lesions and contralateral cerebral cortical lesions can cause motor disturbances in CBS, necessitating the need for bedside examination in patients with CBS.

Keywords: Alzheimer's disease, cerebral cortex, corticobasal syndrome, parkinsonism, striatonigral system

DOI: 10.3233/JAD-131676

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 51-55, 2014

Authors: Delva, Fleur | Auriacombe, Sophie | Letenneur, Luc | Foubert-Samier, Alexandra | Bredin, Alain | Clementy, Anne | Latxague, Chrystelle | Puymirat, Emmanuel | Ballan, Guillaume | Delabrousse-Mayoux, Jean-Phillipe | Glénisson, Laurent | Mazat, Lise | Spampinato, Umberto | Rainfray, Muriel | Tison, François | Dartigues, Jean-François

Article Type: Research Article

Abstract: Background: Knowledge of functional evolution in dementia is crucial for the patients and their families as well as the clinician. Objective: This review identifies scales and outcomes used to describe the natural history of functional decline and describes the natural history of functional decline in a representative clinical population sample of published studies of patients with Alzheimer’s disease (AD). Methods: A search of three relevant databases was conducted and limited to articles published in English and French between 1998 to March 2012, using the keywords “Dementia”, “Activities of Daily Living”, “Instrumental Activities of Daily Living”, “Functional …Impairment”, “Prognosis”, and “Disease Progression”. Results: The search strategy displayed 683 articles, 20 of which were found to be related to the functional evolution of AD. In these studies, different scales were used to describe the evolution of the functional decline, except for the decline of instrumental activities, for which the Lawton scale was used in all studies. Thus, it is difficult to represent the evolution of the functional decline from a clinical point of view. Conclusion: Relatively little data are available to estimate the functional evolution of AD. A consensus with broadened thought is required to know if the progression of the incapacities in these scales is additive or hierarchical. Show more

Keywords: Activities of daily living, Alzheimer's disease, prognosis, review

DOI: 10.3233/JAD-131862

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 57-67, 2014

Authors: Feld, Mariana | Krawczyk, María C. | Sol Fustiñana, M. | Blake, Mariano G. | Baratti, Carlos M. | Romano, Arturo | Boccia, Mariano M.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) can be considered as a disease of memory in its initial clinical stages. Amyloid-β (Aβ) peptide accumulation is central to the disease initiation leading later to intracellular neurofibrillary tangles (NFTs) of cytoskeletal tau protein formation. It is under discussion whether different Aβ levels of aggregation, concentration, brain area, and/or time of exposure might be critical to the disease progression, as well as which intracellular pathways it activates. The aim of the present work was to study memory-related early molecular and behavioral alterations in a mouse model of AD, in which a subtle deregulation of the physiologic function …of Aβ can be inferred. For this purpose we used triple-transgenic (3xTg) mice, which develop Aβ and tau pathology resembling the disease progression in humans. Memory impairment in novel object recognition task was evident by 5 months of age in 3xTg mice. Hippocampus and prefrontal cortex extra-nuclear protein extracts developed differential patterns of Aβ aggregation. ERK1/MAPK showed higher levels of cytosolic activity at 3 months and higher levels of nuclear activity at 6 months in the prefrontal cortex. No significant differences were found in JNK and NF-κB activity and in calcineurin protein levels. Finally, intra-PFC administration of a MEK inhibitor in 6-month-old 3xTg mice was able to reverse memory impairment, suggesting that ERK pathway alterations might at least partially explain memory deficits observed in this model, likely as a consequence of memory trace disruption. Show more

Keywords: 3xTg mice, Alzheimer's disease, amyloid-β aggregation, calcineurin, ERK, JNK, NF-κB, object recognition memory

DOI: 10.3233/JAD-131076

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 69-82, 2014

Authors: Janicki, Sarah C. | Park, Naeun | Cheng, Rong | Lee, Joseph H. | Schupf, Nicole | Clark, Lorraine N.

Article Type: Research Article

Abstract: Background: Few studies of gene variants that affect estrogen activity investigate their association with age at onset of Alzheimer’s disease (AD) in women of different ethnicities. We investigated the influence of ESR2 polymorphisms on age at onset of AD in a multiethnic cohort of women. Objectives: To determine whether gene variants would affect risk for AD differently in women of different population ancestries. Methods: Among 1,686 women participating in the Washington Heights Inwood Columbia Aging Project (WHICAP), association with risk for AD was assessed for 20 ESR2 single-nucleotide polymorphisms (SNPs) using multivariate logistic regression, adjusting for …age at time of study enrollment, presence of an APOE 𝜀4 allele, years of education, and body mass index. Results: Increased risk for AD was associated with four ESR2 SNPs in women of predominantly Caucasian AIMS-defined ancestry: rs944045, rs1256062, rs10144225, and rs2274705 (OR range 1.6–1.9, empiric p-value range 0.002–0.004). A separate SNP (rs10137185) was associated with decreased risk for AD in women who identified themselves as Black (OR 0.6, 95% CI = 0.4–0.9). When vascular risk factors were included in the model, a separate SNP (rs1256059) was associated with increased risk for AD in women of admixed/Hispanic ancestry (OR 1.5, 95% CI = 1.1–2.4). Conclusions: ESR2 polymorphisms affect risk for AD in women, and risk alleles vary by AIMs-defined ancestry and self-identified ethnicity. These effects are possibly due to different linkage disequilibrium patterns or differences in comorbid risk factors mediating SNP effect on risk for AD by group. Show more

Keywords: Alzheimer's disease, estrogen receptor 2, estrogen receptors beta, genetic association studies, Hispanic, women

DOI: 10.3233/JAD-130551

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 83-93, 2014

Authors: Rembach, Alan | Watt, Andrew D. | Wilson, William J. | Villemagne, Victor L. | Burnham, Samantha C. | Ellis, Kathryn A. | Maruff, Paul | Ames, David | Rowe, Christopher C. | Macaulay, S. Lance | Bush, Ashley I. | Martins, Ralph N. | Masters, Colin L. | Doecke, James D. | the AIBL Research Group

Article Type: Research Article

Abstract: Background: We evaluated the utility of longitudinal measures of plasma amyloid-β (Aβ) as a means to identify pre-symptomatic cognitive decline in Alzheimer’s disease (AD) when coupled to neuroimaging and neuropsychological parameters. Methods: Participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were grouped based upon cognitive change and changes in measurable levels of neocortical amyloid over 36 months. Participants were classified as those who transitioned for cognitive decline and change in neocortical amyloid, those healthy controls that did not transition, and stable AD participants over 36 months. Results: Comparisons of plasma Aβ levels between the …transition and non-transitional groups showed Aβ1-42 and the Aβ1-42 /Aβ1-40 ratio were significantly decreased at baseline (p = 0.008 and p = 0.002, respectively) and at 18 months (p = 0.003 and p = 0.004, respectively). Both measures of neocortical amyloid and two previously published composite scores validated the creation of the novel transitional grouping (p < 0.0001). In addition Aβn-42 performed well as a longitudinal prognostic indicator of transition toward cognitive decline, with a significant decrease in the transition group at the 18 month time point (p = 0.01). Conclusion: We demonstrated that baseline plasma Aβ1-42 and the Aβ1-42 /Aβ1-40 ratio were putative biomarkers indicative of cognitive decline and validated this result using 18 month data. We created a novel transitional grouping and validated this measure using published measures of neocortical amyloid and composite memory scores. These findings suggest that longitudinal plasma Aβ could contribute to a pre-symptomatic biomarker panel for AD. Show more

Keywords: Alzheimer's disease, biomarkers, diagnosis, neocortical amyloid burden, Pittsburgh compound B, plasma amyloid-β, positron emission topography

DOI: 10.3233/JAD-131802

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 95-104, 2014

Authors: Bamji-Mirza, Michelle | Callaghan, Debbie | Najem, Dema | Shen, Shanshan | Hasim, Mohamed Shaad | Yang, Ze | Zhang, Wandong

Article Type: Research Article

Abstract: One of the hallmarks of Alzheimer's disease (AD) is the accumulation and deposition of amyloid-β (Aβ) peptides in the brain and cerebral vasculature. Aβ evokes neuroinflammation and has been implicated in insulin signaling disruption and JNK-AP1 activation, contributing to AD neuropathologies including oxidative injury and vascular insufficiencies. In this study we aim to better understand the protective mechanisms of insulin signaling and JNK-AP1 inhibition on the adverse effects of Aβ. Four-hour treatment of hCMEC/D3, the immortalized human brain endothelial cells (iHBEC), with Aβ1-42 resulted in significant c-Jun phosphorylation, oxidative stress, and cell toxicity. Concurrent treatment with Aβ1-42 and …insulin or Aβ1-42 and JNK inhibitor SP600125 significantly improved cell viability. Cytokine array on conditioned media showed that insulin and SP600125 strongly reduced all Aβ1-42 -induced cytokines. ELISA confirmed the protective effect of insulin and SP600125 on Aβ-induced expression of interleukin (IL)-8 and Growth related oncogene-α (Gro-α). qRT-PCR revealed that insulin and SP600125 protected iHBEC from Aβ1-42 -induced inflammatory gene expression. Transcription factor profiling showed that treatment of iHBEC with Aβ1-42 , insulin, or SP600125 alone or in combination resulted in profound changes in modulating the activities of multiple transcription factors and relevant pathways, some of which were validated by western blot. Insulin treatment and JNK inhibition in vitro synergistically reduced c-Jun phosphorylation and thus JNK-AP1 signaling activation. The study suggests that activation of insulin and blocking of JNK-AP1 signaling inhibits Aβ-induced dysregulation of insulin signaling and inflammatory response. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, inflammatory response insulin signaling, JNK-AP1 signaling

DOI: 10.3233/JAD-131949

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 105-122, 2014

Authors: Sun, Xuan | Liang, Ying | Wang, Jun | Chen, Kewei | Chen, Yaojing | Zhou, Xiaoqing | Jia, Jianjun | Zhang, Zhanjun

Article Type: Research Article

Abstract: White matter lesions (WMLs) are of considerable research interest because of their high prevalence and serious consequences, such as stroke and dementia. Most existing studies of WMLs have focused on severe WMLs, but mild WMLs, which are clinically and fundamentally significant, have been largely neglected. The present study is a comprehensive investigation on the injury pattern and on the anatomical, functional, and cognitive changes related to mild WMLs. These results may provide better understanding mild WMLs. Fifty-one human subjects with mild WMLs and 49 control participants completed serial neuropsychological tests and underwent a 3-T magnetic resonance imaging (MRI) scan that …included diffusion tensor imaging, a resting-state functional MRI, and a structural MRI. We found declines in cognitive functions such as global function, executive function, and episodic memory in mild WMLs subjects. The white matter injuries in the mild WMLs subjects were mainly in the fibers that projected to frontal areas, while gray matter structures were relatively intact. The overall resting state function of the frontal area was significantly increased. The integrity of the neural fibers in the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus was significantly correlated with the cognitive scores in executive function and episodic memory in both the control and the mild WMLs group. These findings demonstrate that mild WMLs subjects exhibit abnormalities in both white matter structure and functional intrinsic brain activity and that such changes are related to several types of cognitive dysfunction. Show more

Keywords: Cognition, diffusion tensor imaging, mild white matter lesions, resting-state functional magnetic resonance imaging

DOI: 10.3233/JAD-131709

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 123-134, 2014

Authors: Gerschütz, Anne | Heinsen, Helmut | Grünblatt, Edna | Wagner, Anne Kristin | Bartl, Jasmin | Meissner, Christoph | Fallgatter, Andreas J. | Al-Sarraj, Safa | Troakes, Claire | Ferrer, Isidro | Arzberger, Thomas | Deckert, Jürgen | Riederer, Peter | Fischer, Matthias | Tatschner, Thomas | Monoranu, Camelia Maria

Article Type: Research Article

Abstract: The hallmarks of sporadic Alzheimer's disease (AD) are extracellular amyloid deposits, intracellular neurofibrillary tangles (NFTs), and neuronal death. Hyperphosphorylation of tau is a key factor in the generation of NFTs. Mitogen activated protein kinase 1 (MAPK1) and protein kinase C beta (PRKCB) are thought to play a role in hyperphosphorylation, and PRCKB is thought to be involved in hypoxic stress and vascular dysfunction, and to trigger MAPK phosphorylation pathways. We performed single-cell analyses of neurons with different vulnerabilities to AD-related changes. Using quantitative PCR (qPCR), we measured the levels of MAPK1 and PRKCB transcript in CA1 (high vulnerability), CA2 pyramidal …cells from the hippocampus, granule cells from the cerebellum (low vulnerability), and neurons from the brain stem (nucleus tractus spinalis nervi trigemini, characterized by early neurophysiological deficits) at progressive Braak stages compared to age-matched controls. The highly vulnerable CA1 pyramidal neurons were characterized by age- and disease-unrelated increases in PRCKB levels and by age- and disease-related increases in MAPK1 levels. In contrast, low PRKCB levels were found in CA2 pyramidal neurons, and MAPK1 levels were elevated in controls and intermediate AD stages. Both PRKCB and MAPK1 were increased in the late AD stages. MAPK1 and PRKCB levels were low in the brainstem and cerebellum. We propose that alterations in the expression of these two genes occur early in the pathogenesis of AD in a region-specific manner. In addition, multiple signal transduction pathways need to be affected to result in AD instead of physiological aging. Show more

Keywords: Alzheimer's disease, MAPK1, neurodegeneration, PRKCB, selective vulnerability, signal transduction pathway

DOI: 10.3233/JAD-131280

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 135-142, 2014

Authors: Pérez, Mar | Cuadros, Raquel | Pallas-Bazarra, Noemi | García, Carlos | Langa, Elena | Jurado-Arjona, Jerónimo | Hernández, Félix | Avila, Jesús

Article Type: Research Article

Abstract: We modified tau protein with boronic acid to facilitate its delivery into non neural or neural cultured cells lacking tau protein. Our results indicate that the incorporated tau promotes the formation of cytoplasmic extensions in non-neuronal cells, as well as the appearance of neurites in cultured tau knockout hippocampal neurons. In addition, boronated tau is incorporated into hippocampal neurons of tau knockout mice after intracranial injection in vivo. These findings describe a novel method to deliver exogenous tau protein into cells.

Keywords: Boronic acid, protein delivery, tau protein

DOI: 10.3233/JAD-131655

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 143-151, 2014

Authors: Zhang, Jian | Zhang, Chun-Hua | Li, Rong-Jie | Lin, Xiao-Li | Chen, Ying-Dao | Gao, Huai-Qing | Shi, Sheng-Liang

Article Type: Research Article

Abstract: Background: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been reported to have high diagnostic accuracy in patients with Alzheimer’s disease (AD). Objective: To determine the diagnostic accuracy of urinary AD7c-NTP for the diagnosis of AD in patients with suspected AD. Methods: We searched MEDLINE (January 1950 to date) and other electronic databases (from inception to date) for diagnostic accuracy studies that compared urinary AD7c-NTP to the standard clinical diagnosis of AD. We conducted citation searches and screened the reference lists of included studies. Studies were assessed for methodological quality using QUADAS. Summary receiver operating characteristic curves were …used to summarize overall test performance. Result: Nine studies met our inclusion criteria. The summary estimates of the urinary AD7c-NTP assay for probable or possible AD were as follows: SEN, 0.87 (95%CI: 0.80–0.91); SPE, 0.89 (95%CI: 0.87–0.91); PLR, 8.13 (95% CI: 6.60–10.02); and NLR, 0.15 (95% CI: 0.10–0.22). The four summary estimates of urinary AD7c-NTP assay for probable AD were 0.89 (95% CI: 0.86–0.92), 0.90 (95% CI: 0.88–0.92), 8.88 (95% CI: 7.09–11.12), and 0.12 (95% CI: 0.09–0.16), with no obvious heterogeneity. Conclusion: Urinary AD7c-NTP is a sensitive and specific test for the diagnosis of probable AD. However, whether urinary AD7c-NTP can be used as an early marker is still unknown. Show more

Keywords: AD7c-NTP, Alzheimer's disease, biomarker, meta-analysis, urine

DOI: 10.3233/JAD-131445

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 153-159, 2014

Authors: Meckler, Xavier | Checler, Frédéric

Article Type: Research Article

Abstract: γ-secretase is involved in the regulated intramembrane proteolysis of amyloid-β protein precursor (AβPP) and of many other important physiological substrates. γ-secretase is a multiproteic complex made of four main core components, namely presenilin 1 or 2, APH-1, PEN-2, and Nicastrin. Since APH-1 exists as different variants, combinations of these proteins can theoretically yield distinct γ-secretase complexes. Whether γ-secretase complexes trafficking and targeting to either similar or distinct subcellular compartments depend upon their molecular composition remains unknown. A differential complex-specific distribution may drive a narrow specificity for a subset of substrates that would traffic within the same cellular compartments. Here, we …generated bigenic expression vectors to co-express untagged nicastrin or presenilin 1 together with either PEN-2 or distinct variants of APH-1 (aL, aS and b) tagged with complementary fragments of the fluorescent protein Venus. We show that these constructs allow the formation of functional γ-secretase complexes and their visualization with bimolecular fluorescence complementation (BiFC). BiFC can be detected at the plasma membrane as well as in endosomes/lysosomes in addition to the endoplasmic reticulum (ER) of COS-7 cells transfected with the different variants of APH-1. However, the majority of cells co-transfected with APH-1b presented BiFC signal only in the ER, suggesting enhanced retention/retrieval of APH-1b-containing γ-secretase complexes. Therefore, the new tools described here should be helpful to decipher the precise subcellular trafficking of γ-secretase complexes and to delineate the distinct variant-linked pathways in various cellular systems. Show more

Keywords: APH-1, fluorescence microscopy, γ-secretase, nicastrin, PEN-2, presenilin, transmembrane protein transport

DOI: 10.3233/JAD-131268

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 161-176, 2014

Authors: Bayer, Antony | Phillips, Michelle | Porter, Gillian | Leonards, Ute | Bompas, Aline | Tales, Andrea

Article Type: Research Article

Abstract: Although there is some evidence that amnestic mild cognitive impairment (aMCI) can be characterized by significant deficits in visuospatial function, the cross-sectional design of the majority of these studies renders it impossible to determine whether such deficits occur in aMCI as a result of, or accompany, amnestic dysfunction per se or whether they are the result of disproportionately poorer performance in a sub-group of patients for whom aMCI represents prodromal dementia. Similarly, whether the absence of aMCI-related functional deficit stems from the masking of dementia-specific abnormality by the preserved performance of those with a different cause of aMCI cannot be …ascertained. Here we report the outcome of a cross-sectional and 2.5-year longitudinal evaluation follow-up, computer-based study of visuospatial attention, specifically attentional disengagement and inhibition of return and the mean (RTSPEED ) and intra-individual variability (IIVRT ) of their component reaction times, in 45 patients with aMCI and 31 cognitively healthy older adults. Reduced inhibition of return (p = 0.01 and p = 0.037 in response to 400 and 800 ms cue to target interval conditions), slowed RTSPEED (p = 0.038 and p = 0.03 in response to 400 and 800 ms cue), and raised IIVRT at baseline testing (p = 0.003, p = 0.026, p = 0.013 in response to 200, 400 and 800 ms cue) were associated with the development of dementia within the 2.5-year follow-up period, whereas the performance of patients with aMCI who did not develop dementia did not differ significantly from that of the cognitively healthy controls. Attentional disengagement appeared insensitive to the presence of prodromal dementia or amnestic dysfunction per se. The results indicate that those patients for whom aMCI represents prodromal dementia may experience, in addition to amnestic dysfunction, a decline in the functional integrity of some fundamental aspects of visual information processing, an effect potentially capable of increasing disease burden and reducing quality of life. Show more

Keywords: Aging, attentional disengagement, inhibition of return, mild cognitive impairment, methodology, reaction time, visual attention

DOI: 10.3233/JAD-131934

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 177-189, 2014

Authors: Solberg, Nathan O. | Chamberlin, Ryan | Vigil, Jenette R. | Deck, Lorraine M. | Heidrich, John E. | Brown, David C. | Brady, Christina I. | Vander Jagt, Thomas A. | Garwood, Michael | Bisoffi, Marco | Severns, Virginia | Vander Jagt, David L. | Sillerud, Laurel O.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is associated with a microglia-dependent neuroinflammatory response against plaques containing the fibrous protein amyloid-β (Aβ). Activation of microglia, which closely associate with Aβ plaques, engenders the release of pro-inflammatory cytokines and the internalization of Aβ fibrils. Since the pro-inflammatory transcription factor NF-κB is one of the major regulators of Aβ-induced inflammation, we treated transgenic amyloid-β protein protein/presenilin-1 (AβPP/PS1) mice for one year with a low dose (0.01% by weight in the diet) of either of two trans-stilbene NF-κB inhibitors, resveratrol or a synthetic analog LD55. The 3D distribution of Aβ plaques was measured ex vivo in intact …brains at 60 μm resolution by quantitative magnetic resonance imaging (MRI) using blood-brain barrier-permeable, anti-AβPP-conjugated superparamagentic iron oxide nanoparticles (SPIONs). The MRI measurements were confirmed by optical microscopy of thioflavin-stained brain tissue sections and indicated that supplementation with either of the two trans-stilbenes lowered Aβ plaque density in the cortex, caudoputamen, and hippocampus by 1.4 to 2-fold. The optical measurements also included the hippocampus and indicated that resveratrol and LD55 reduced average Aβ plaque density by 2.3-fold and 3.1-fold, respectively. Ex vivo measurements of the regional distribution of microglial activation by Iba-1 immunofluorescence of brain tissue sections showed that resveratrol and LD55 reduced average microglial activation by 4.2- fold and 3.5-fold, respectively. Since LD55 lacked hydroxyl groups but both resveratrol and LD55 concomitantly reduced both Aβ plaque burden and neuroinflammation to a similar extent, it appears that the antioxidant potential of resveratrol is not an important factor in plaque reduction. Show more

Keywords: LD55, magnetic resonance imaging, microglia, neuroinflammation, NF-κB, resveratrol, SPIONs, transgenic mice

DOI: 10.3233/JAD-131031

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 191-212, 2014

Authors: Minati, Ludovico | Chan, Dennis | Mastropasqua, Chiara | Serra, Laura | Spanò, Barbara | Marra, Camillo | Caltagirone, Carlo | Cercignani, Mara | Bozzali, Marco

Article Type: Research Article

Abstract: We investigated changes in functional network architecture in amnestic mild cognitive impairment using graph-based analysis of task-free functional magnetic resonance imaging and fine cortical parcellation. Widespread disconnection was observed primarily in cortical hubs known to manifest early Alzheimer's disease pathology, namely precuneus, parietal lobules, supramarginal and angular gyri, and cuneus, with additional involvement of subcortical regions, sensorimotor cortex and insula. The connectivity changes determined using graph-based analysis significantly exceed those detected using independent component analysis both in amplitude and topographical extent, and are largely decoupled from the presence of overt atrophy. This superior ability of graph-based analysis to detect disease-related …disconnection highlights its potential use in the determination of biomarkers of early dementia. Graph-based analysis source code is provided as supplementary material. Show more

Keywords: Amnestic mild cognitive impairment (aMCI), functional connectivity, graph theory, prodromal Alzheimer's disease, resting-state functional MRI

DOI: 10.3233/JAD-131766

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 213-220, 2014

Authors: Brodaty, Henry | Connors, Michael H. | Xu, Jing | Woodward, Michael | Ames, David | on behalf of the PRIME study group

Article Type: Research Article

Abstract: Patients with dementia often require institutionalization when they can no longer care for themselves. The study examined demographic and clinical variables that predict the time until institutionalization in patients with dementia attending memory clinics. Of 970 patients recruited from nine memory clinics around Australia, 779 patients had dementia at baseline. Measures of dementia severity, cognition, functional ability, neuropsychiatric symptoms, caregiver burden, and medication use were completed for all patients. Patients were followed for three years. Overall, 197 (25.3%) of the patients with dementia were institutionalized within three years. Lower cognitive ability, lower functional ability, and more neuropsychiatric symptoms at baseline …predicted a shorter time until institutionalization, as did use of antipsychotic medication. In addition, greater deterioration in cognitive ability, functional ability, and neuropsychiatric symptoms over the initial three months predicted a shorter time to institutionalization. The findings confirm that clinical features of dementia at baseline predict the time to institutionalization, as do greater changes in symptoms over three months independent of baseline levels. Show more

Keywords: Alzheimer's disease, dementia, institutionalization, longitudinal, nursing home, survival analysis

DOI: 10.3233/JAD-131850

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 221-226, 2014

Authors: Cuello, A. Claudio

Article Type: Book Review

DOI: 10.3233/JAD-140218

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 227-227, 2014

Article Type: Other

DOI: 10.3233/JAD-131851

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 229-232, 2014