Journal of Alzheimer's Disease - Volume 36, issue 1

Authors: Kincses, Zsigmond Tamas | Hořínek, Daniel | Szabó, Nikoletta | Tóth, Eszter | Csete, Gergő | Štěpán-Buksakowska, Irena | Hort, Jakub | Vécsei, László

Article Type: Research Article

Abstract: Several recent studies have indicated that white matter is affected in Alzheimer's disease (AD). Diffusion tensor imaging is a tool by which the white matter microstructure can be examined in vivo, and might offer a possibility for the identification of the pattern of white matter disintegration in AD. In the current analysis, we made use of a novel model-free analysis approach of linked independent component analysis to identify a motif of diffusion parameter alterations exemplifying AD. Analysis of the diffusion data of 16 AD patients and 17 age-matched healthy subjects revealed six independent components, two of which demonstrated differences between …the patients and controls. Component #0 was dominated by axial diffusivity, but significant alterations in fractional anisotropy and mean and radial diffusivity were also detected. Alterations were found in regions of crossing of major white matter pathways, such as forceps, corona radiate, and superior longitudinal fascicle, as well as medio-temporal white matter. These results lend support to the coexistence of white matter disintegration of the late myelinating associating fibers and wallerian degeneration-related disintegration, in accordance with the retrogenesis and wallerian degeneration hypothesis. Show more

Keywords: Alzheimer's disease, diffusion tensor imaging, linked independent component analysis, magnetic resonance imaging

DOI: 10.3233/JAD-122431

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 119-128, 2013

Authors: Martínez, Eva | Navarro, Ana | Ordóñez, Cristina | del Valle, Eva | Tolivia, Jorge

Article Type: Research Article

Abstract: Apolipoprotein D (Apo D) is a lipid binding protein whose expression is strongly induced in the mammalian brain during aging and age-dependent neurodegenerative diseases such as Alzheimer's disease (AD), where it can play an important function as a neuroprotective and antioxidant protein. Increasing evidence suggests that the gradual increase in free radicals and oxidative stress with age is the primary determinant to aging brain. The aim of this work is to study the effect of hydrogen peroxide (H2 O2 ) in Apo D expression, in hippocampal cells, in order to investigate the relationship between oxidative stress and elevated levels of …Apo D found in hippocampus during aging and AD and also elucidate the possible pathways that lead to this increase. In this study, we demonstrated that Apo D expression in hippocampal neurons of aged and AD brains directly correlates with age-related increase in oxidative stress. More importantly, our results in the HT22 cell line indicate that Apo D protein level increases in a concentration-dependent manner specifically at those H2 O2 concentrations that caused oxidative damage and apoptotic cell death. These data support the idea that oxidative stress-induced apoptosis during aging and AD may be associated with the increment in the expression of Apo D in these situations. Show more

Keywords: Aging, Alzheimer's disease, apolipoprotein D, apoptosis, hippocampal cells, oxidative stress

DOI: 10.3233/JAD-130215

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 129-144, 2013

Authors: Kepe, Vladimir | Bordelon, Yvette | Boxer, Adam | Huang, Sung-Cheng | Liu, Jie | Thiede, Frederick C. | Mazziotta, John C. | Mendez, Mario F. | Donoghue, Natacha | Small, Gary W. | Barrio, Jorge R.

Article Type: Research Article

Abstract: Objective: Currently [18 F]FDDNP is the only PET imaging probe with the ability to visualize hyperphosphorylated tau fibrillar aggregates in living subjects. In this work, we evaluate in vivo [18 F]FDDNP labeling of brain neuropathology, primarily tau fibrillar aggregates, in patients with progressive supranuclear palsy (PSP), a human tauopathy usually lacking amyloid-Κ deposits. Methods: Fifteen patients with PSP received [18 F]FDDNP PET scanning. [18 F]FDDNP distribution volume ratios, in reference to cerebellar gray matter, were determined for cortical and subcortical areas and compared with those of patients with Parkinson’s disease with short disease duration, and age-matched control subjects …without neurodegenerative disorders. Results: [18 F]FDDNP binding was present in subcortical areas (e.g., striatum, thalamus, subthalamic region, midbrain, and cerebellar white matter) regardless of disease severity, with progressive subcortical and cortical involvement as disease severity increased. Brain patterns of [18 F]FDDNP binding were entirely consistent with the known pathology distribution for PSP. High midbrain and subthalamic region [18 F]FDDNP binding was distinctive for PSP subjects and separated them from controls and patients with Parkinson’s disease. Conclusions: These results provide evidence that [18 F]FDDNP is a sensitive in vivo PET imaging probe to map and quantify the dynamic regional localization of tau fibrillar aggregates in PSP. Furthermore, [18 F]FDDNP PET may provide a tool to detect changes in tau pathology distribution either associated with disease progression or as a treatment biomarker for future tau-specific therapies. Patterns of [18 F]FDDNP binding may also be useful in diagnosis early in disease presentation when clinical distinction among neurodegenerative disorders is often difficult. Show more

Keywords: FDDNP, neuropathology, Parkinson's disease, positron emission tomography, progressive supranuclear palsy, tauopathy

DOI: 10.3233/JAD-130032

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 145-153, 2013

Authors: Bittner, Daniel M. | Heinze, Hans-Jochen | Kaufmann, Jörn

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease (AD), levels of N-acetylaspartate (NAA) is diminished and choline (Cho) and myo-inositol (mI) are increased. In cerebrospinal fluid (CSF), tau and phosphoylated tau (p-tau181P ) is increased and amyloid-β(1-42) (Aβ42 ) decreased. Objectives: 1) To compare metabolites of different 1 H-MRS voxels and assess its utility to differentiate AD from controls and to examine the relationship to cognition and to CSF markers. Methods: 17 healthy controls and 19 AD subjects were studied using 1 H-MRS. In the AD cases, additional CSF analysis was obtained. Results: Relative to controls, AD …subjects had reduced NAA/Creatine (Cr) levels in hippocampus (42.3% to 26.0%, p < 0.001), posterior cingulate gyrus (10.4% to 0.2%, p = 0.04), and parietal lobe (14.9% to 3.8%, p = 0.002). Further differences of Cho/Cr and mI/Cr in the hippocampus (Cho/Cr: p = 0.04; mI/Cr: p = 0.015) and posterior cingulate (Cho/Cr: p = 0.001; mI/Cr: p = 0.001) were observed. NAA/Cr of the hippocampus yielded the highest sensitivity (94.1%) and specificity (92.3%) to differentiate AD from controls. NAA/Cr was associated with general cognition (hippocampus: R = 0.68, p < 0.001; parietal lobe: R = 0.57, p = 0.001; posterior cingulate: R = 0.50, p = 0.003). Higher hippocampal NAA/Cr was related to higher CSF Aβ42 , while lower parietal NAA/Cr was associated with a higher CSF total tau (t-tau) and p-tau181P . Posterior cingulate mI/Cr was related to CSF t-tau and NAA/mI. Conclusion: 1 H-MRS is an appropriate measure in AD. Measurement at different regions presumably reflects different pathological changes. Show more

Keywords: Aβ42, Alzheimer's disease, cerebrospinal fluid, hTau, MR spectroscopy, pTau

DOI: 10.3233/JAD-120778

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 155-163, 2013

Authors: Sala-Llonch, Roser | Fortea, Juan | Bartrés-Faz, David | Bosch, Beatriz | Lladó, Albert | Peña-Gómez, Cleofé | Antonell, Anna | Castellanos-Pinedo, Fernando | Bargalló, Nuria | Molinuevo, José Luis | Sánchez-Valle, Raquel

Article Type: Research Article

Abstract: PSEN1 mutations are the most frequent cause of familial Alzheimer's disease and show nearly full penetrance. Here we studied alterations in brain function in a cohort of 19 PSEN1 mutation carriers: 8 symptomatic (SMC) and 11 asymptomatic (AMC). Asymptomatic carriers were, on average, 12 years younger than the predicted age of disease onset. Thirteen healthy subjects were used as a control group (CTR). Subjects underwent a 10-min resting-state functional magnetic resonance imaging (fMRI) scan and also performed a visual encoding task. The analysis of resting-state fMRI data revealed alterations in the default mode network, with increased frontal connectivity and reduced …posterior connectivity in AMC and decreased frontal and increased posterior connectivity in SMC. During task-related fMRI, SMC showed reduced activity in regions of the left occipital and left prefrontal cortices, while both AMC and SMC showed increased activity in a region within the precuneus/posterior cingulate, all as compared to CTR. Our findings suggest that fMRI can detect evolving changes in brain mechanisms in PSEN1 mutation carriers and support the use of this technique as a biomarker in Alzheimer's disease, even before the appearance of clinical symptoms. Show more

Keywords: Alzheimer's disease, default mode network, functional magnetic resonance imaging, presenilin1, visual memory

DOI: 10.3233/JAD-130062

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 165-175, 2013

Authors: Fernandez, Roberto | Monacelli, Anthony | Duffy, Charles J.

Article Type: Research Article

Abstract: Background: Aging and Alzheimer’s disease (AD) disrupt visuospatial processing and visual motion evoked potentials in a manner linked to navigational deficits. Objective: Our goal is to determine if aging and AD have distinct effects on visual cortical motion processing for navigation. Methods: We recorded visual motion event related potentials (ERPs) in young (YNC) and older normal controls (ONC), and early AD patients (EADs) who viewed rapidly changing optic flow stimuli that simulate naturalistic changes in heading direction, like those that occur when following a path of self-movement through the environment. After a random series of optic …flow stimuli, a vertical motion stimulus was presented to verify sustained visual attention by demanding a rapid push-button response. Results: Optic flow evokes robust ERPs that are delayed in aging and diminished in AD. The interspersed vertical motion stimuli yielded shorter N200 latencies in EADs, matching those in ONCs, but the EADs’ N200 amplitudes remained small. Conclusions: Aging and AD have distinct effects on visual sensory processing: aging delays evoked response, whereas AD diminishes responsiveness. Show more

Keywords: Aging, Alzheimer's disease, event related potentials, motion, vision

DOI: 10.3233/JAD-122053

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 177-183, 2013

Authors: Cheng, Xiang-Shu | Zhao, Kun-Peng | Jiang, Xia | Du, Lai-Ling | Li, Xiao-Hong | Ma, Zhi-Wei | Yao, Jun | Luo, Yu | Duan, Dong-Xiao | Wang, Jian-Zhi | Zhou, Xin-Wen

Article Type: Research Article

Abstract: The activity of protein phosptase-2A (PP2A) is significantly decreased in the brains of Alzheimer's disease (AD) patients, but the upstream effectors for regulating PP2A activity are not fully understood. Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) is a key enzyme involved in energy metabolism and its gene expression level is reduced in AD brain specimens. Whether Nmnat2 can activate PP2A deserves to be explored. Here, we first measured the level of Nmnat2, Tyr307-phosphorylation of PP2A, and tau phosphorylation in Tg2576 mice. We observed that the mRNA and protein levels of Nmnat2 were significantly decreased with a simultaneous elevation of p-Tyr307-PP2A and tau …phosphorylation in Tg2576 mice. Further studies in HEK293 cells with stable expression of human tau441 (HEK293/tau) demonstrated that simultaneous inhibition of PP2A by okadaic acid abolished the Nmnat2-induced tau dephosphorylation. Moreover, we further demonstrated that overexpression of Nmnat2 could activate PP2A with attenuation of tau phosphorylation, whereas downregulation of Nmnat2 by shRNA inhibited PP2A with tau hyperphosphorylation at multiple AD-associated sites. Our data provide the first evidence that Nmnat2 affects tau phosphorylation by regulating PP2A activity, suggesting that Nmnat2 may serve as a potential target in arresting AD-like tau pathologies. Show more

Keywords: Nicotinamide mononucleotide adenylyltransferase 2, phosphorylation, protein phosphatase 2A, tau

DOI: 10.3233/JAD-122173

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 185-195, 2013

Authors: Hodgson, Nathaniel | Trivedi, Malav | Muratore, Christina | Li, Shaomin | Deth, Richard

Article Type: Research Article

Abstract: Oxidative stress, hyperhomocysteinemia, altered DNA methylation, and insulin resistance in the brain are associated with Alzheimer's disease (AD), but the role of amyloid-β (Aβ) in these events remains unclear. Intracellular cysteine is rate-limiting for synthesis of the antioxidant glutathione (GSH), and factors regulating cysteine uptake exert a powerful influence over cellular redox status, especially in mature neurons where cysteine synthesis via transsulfuration of homocysteine (HCY) is restricted. We investigated the effect of soluble Aβ oligomers (oAβ) on basal and insulin-like growth factor-1 (IGF-1)-induced cysteine uptake mediated by the excitatory amino acid transporter 3 (EAAT3) in cultured human neuronal cells. We …also examined the effect of oAβ on intracellular thiol metabolite levels, DNA methylation, and the transcription status of redox and methylation-associated genes. oAβ inhibited EAAT3-mediated cysteine uptake, causing a decrease in intracellular cysteine and GSH levels. The ratio of the methyl donor S-adenosylmethionine to the methylation inhibitor S-adenosylhomocysteine was decreased, in association with an increase in HCY and a global decrease in DNA methylation, indicative of decreased activity of the redox-sensitive enzyme methionine synthase. These metabolic effects of oAβ coincided with changes in the expression of redox and methylation pathway genes. The ability of oAβ to modulate gene expression via their redox and methylation-dependent epigenetic effects may contribute to the pathology of AD and recognition of this mechanism may lead to novel treatment approaches. We describe a role of IGF-1 signaling in regulating redox and methylation homeostasis, and propose this to be a pathogenic target of oAβ. Show more

Keywords: Alzheimer's disease, epigenomics, glutathione, insulin-like growth factor 1,5-methyltetrahydrofolate-homocysteine s-methyltransferase

DOI: 10.3233/JAD-130101

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 197-209, 2013

Authors: Pérez-Grijalba, Virginia | Pesini, Pedro | Monleón, Inmaculada | Boada, Mercè | Tárraga, Lluís | Ruiz-Laza, Agustín | Martínez-Lage, Pablo | San-José, Itziar | Sarasa, Manuel

Article Type: Research Article

Abstract: Validation of cost-effective, non-invasive methods to identify early (pre-clinical) Alzheimer's disease (AD) is increasingly becoming a key research challenge. We have developed two ELISA sandwich colorimetric tests for the accurate detection of amyloid-β (Aβ)1-40 and Aβ1-42 : i) directly accessible (DA) in the plasma, ii) recovered from the plasma sample (RP) after diluting the plasma sample in a formulated buffer, and iii) associated with the remaining cellular pellet (CP). These tests were carried out on samples from healthy controls (n = 19) and individuals with mild cognitive impairment (MCI; n = 27) with amnestic-hippocampal syndrome to investigate whether this …comprehensive approach may help to explain the association between blood Aβ levels and MCI. A logistic regression analysis detected seven direct or calculated markers (CP 40, DA 42, RP 42, DA/CP 40, DA/RP 42, DA/CP 42, and DA 42/40) with significant odds ratios (OR) after they were dichotomized with regard to the median of the pooled population. In particular, the likelihood [OR (95% CI)] of having MCI for patients with catCP 40, catDA/RP 42, catDA/CP 42, or catDA 42/40 below the corresponding population median (“positive test”) was 11.48 (1.87–70.52), 22.09 (3.19–152.61), 11.48 (1.87–70.50), and 9.54 (1.77–51.38)-fold higher, respectively, than in those with a “negative test” after adjusting for the effect of the ApoE genotype. These results are congruent with the hypothesis that changes in blood Aβ levels may be associated with the initial stages of AD. Thus, these Aβ blood biomarkers might be useful tools for screening for those at increased risk of developing AD. Show more

Keywords: Aging, Alzheimer's disease, diagnosis, ELISA

DOI: 10.3233/JAD-121744

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 211-219, 2013

Article Type: Other

DOI: 10.3233/JAD-130102

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 221-223, 2013