Journal of Alzheimer's Disease - Volume 42, issue 1

Authors: Roy, Kamolika | Pepin, Lesley C. | Philiossaint, Marlie | Lorius, Natacha | Becker, J. Alex | Locascio, Joseph J. | Rentz, Dorene M. | Sperling, Reisa A. | Johnson, Keith A. | Marshall, Gad A. | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Impairment in instrumental activities of daily living (IADL) begins as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer’s disease (AD) dementia. IADL impairment in AD dementia has been associated with inferior parietal, inferior temporal, and superior occipital hypometabolism using 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Objective: To investigate the relationship between regional FDG metabolism and IADL in clinically normal (CN) elderly, MCI, and mild AD dementia subjects cross-sectionally and longitudinally. Methods: One hundred and four CN, 203 MCI, and 95 AD dementia subjects from the Alzheimer’s Disease Neuroimaging Initiative underwent clinical assessments …every 6 to 12 months for up to three years and baseline FDG PET. The subjective, informant-based Functional Activities Questionnaire was used to assess IADL. General linear models and mixed effects models were used, covarying for demographics, cognition, and behavior. Results: The cross-sectional analysis revealed middle frontal and orbitofrontal hypometabolism were significantly associated with greater IADL impairment. Additionally, the interaction of diagnosis with posterior cingulate and with parahippocampal hypometabolism showed a greater decline in IADL performance as metabolism decreased for the AD dementia relative to the MCI group, and the MCI group relative to the CN group. The longitudinal analysis showed that baseline middle frontal and posterior cingulate hypometabolism were significantly associated with greater rate of increase in IADL impairment over time. Conclusion: These results suggest that regional synaptic dysfunction, including the Alzheimer-typical medial parietal and less typical frontal regions, relates to daily functioning decline at baseline and over time across the early AD spectrum. Show more

Keywords: 18F-fluorodeoxyglucose positron emission tomography, Alzheimer's disease, instrumental activities of daily living, mild cognitive impairment

DOI: 10.3233/JAD-131796

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 291-300, 2014

Authors: Martin, Carolina | Leyton, Luis | Arancibia, Yennyfer | Cuevas, Alexei | Zambrano, Angara | Concha, Margarita I. | Otth, Carola

Article Type: Research Article

Abstract: Currently, it is unclear whether a neuron that undergoes viral reactivation and produces infectious particles survives and resumes latency or is killed, which is intriguing even if still unanswered. Previous reports have shown that herpes simplex virus type 1 (HSV-1) inhibits apoptosis during early infection, but is pro-apoptotic during productive infection. Taking in consideration that the stress sensors AMPK and Sirt1 are involved in neuronal survival and neuroprotection, we hypothesized that HSV-1 could activate the AMPK/Sirt1 axis as a strategy to establish latency through inhibition of apoptosis and restoration of the energy status. These effects could be accomplished through deacetylation …of pro-apoptotic protein p53 and regulation of the master regulator of mitochondrial biogenesis and function PGC-1α and its target gene TFAM. Accordingly, we evaluated the AMPK/Sirt1 axis and its targets p53, PGC-1α, and acetyl CoA carboxylase in mice neuronal cultures infected with HSV-1 by western blot, RT-qPCR, and immunofluorescence analyses. Herein, we show that HSV-1 differentially modulates the AMPK/Sirt1 axis during the course of infection. In fact, during early infection (2 hpi) activated AMPK (p-AMPK) was down-regulated, but thereafter recovered gradually. In contrast, the levels of acetylated-p53 increased during the first hours post infection, but afterwards were reduced in parallel with the activation of Sirt1. However, acetylated-p53 peaked again at 18 hpi during productive infection, suggesting an activation of apoptosis. Strikingly, acetylated-p53, Sirt1, and p-AMPK apparently translocate from the nucleus to the cytoplasm after 4 hpi, where they accumulate in discrete foci in the perinuclear region. These results suggest that HSV-1 modulates the AMPK/Sirt1 axis differentially during the course of infection interfering with pro-apoptotic signaling and regulating mitochondrial biogenesis. Show more

Keywords: AMPK, HSV-1, p53, PGC-1α, Sirt1

DOI: 10.3233/JAD-140237

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 301-312, 2014

Authors: Ghosh, Debolina | Brewer, Gregory J.

Article Type: Research Article

Abstract: The extracellular redox environment of cells is mainly set by the redox couple cysteine/cystine (cys/cySS) while intracellular redox is buffered by reduced/oxidized glutathione (GSH/GSSG), but controlled by NAD(P)H/NAD(P). With aging, the extracellular redox environment shifts in the oxidized direction beyond middle-age. Since aging is the primary risk factor in Alzheimer's disease (AD), here our aim was to determine if a reduced extracellular cys/cySS redox potential of cultured primary mouse neurons changes the intracellular redox environment, affects pAkt levels, and protects against neuron loss. A reductive shift in cys/cySS in the extracellular medium of neuron cultures from young (4 month) and …old (21 month) neurons from non-transgenic) and triple transgenic AD-like mice (3xTg-AD) caused an increase in intracellular NAD(P)H and GSH levels along with lower reactive oxygen species levels. Importantly, the imposed reductive shift decreased neuron death markedly in the 21 month neurons of both genotypes. Moreover, a reduced cys/cySS redox state increased the pAkt/Akt ratio in 21 month aging and AD-like neurons that positively correlated with a decreased neuron loss. Our findings demonstrate that manipulating the extracellular redox environment toward a more reduced redox potential is neuroprotective in both aging and AD-like neurons and may be a powerful and pragmatic therapeutic tool in aging and age-related diseases like AD. Show more

Keywords: Aging, Alzheimer's disease, Akt, cys/cySS, glutathione, NAD(P)H, neurodegeneration

DOI: 10.3233/JAD-132756

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 313-324, 2014

Authors: Olazarán, Javier | González, Belén | Osa-Ruiz, Emma | Felipe-Ruiz, Silvia | Boyano, Inmaculada | Fontani, Vania | Castagna, Alessandro | Mendoza, Carolina | Zea, María Ascensión | Frades, Belén | Rinaldi, Salvatore | Martínez-Martín, Pablo

Article Type: Research Article

Abstract: We conducted a randomized, cross-over trial to investigate the feasibility, safety, and motor effects of brain stimulation with radio electric asymmetric conveyer (REAC) technique in patients with Alzheimer's disease (AD). Neuropostural optimization (NPO) and sham protocol were administered to 60 patients from the nursing home and day care units of the Alzheimer Center Reina Sofía Foundation. The mean age was 84.1 (SD 7.9) years and 86.7% of the subjects were female. Motor measures were collected at baseline (T1), immediately (T2), seven (T3), and 11 days (T4) after treatment and, following cross-over, immediately (T5), seven (T6), and 11 (T7) days after …treatment. Close safety surveillance was conducted from seven days before T1 to the end of the study (T7), with total study duration of 35 days. Wilcoxon test was utilized in the efficacy analysis, considering T1 and T5 as independent baseline assessments and using a threshold of p < 0.05 (corrected) for statistical significance. The NPO protocol was easily administered and well accepted by the participants. Axial movements improved at T3 and T4 after NPO and at T2 after sham NPO, but no significant effects were observed in axial movements in the second phase of the trial. The effects of NPO in gait performance were not consistent. There were six falls between T2 and T7, but only two of them occurred in patients who had received NPO. In light of safety and feasibility of REAC, a trial with the more intense neuropsycho-physical optimization protocol is warranted. Show more

Keywords: Alzheimer's disease, brain stimulation, gait dysfunction, motor performance, neuro postural optimization, nursing homes, radio electric asymmetric conveyer

DOI: 10.3233/JAD-140417

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 325-332, 2014

Authors: Vangavaragu, Jhansi Rani | Valasani, Koteswara Rao | Fang, Du | Williams, Todd D. | Yan, Shirley ShiDu

Article Type: Research Article

Abstract: A major obstacle to the development of effective treatment of Alzheimer's disease (AD) is successfully delivery of drugs to the brain. We have previously identified a series of benzothiazole phosphonate compounds that block the interaction of amyloid-β peptide with amyloid-β binding alcohol dehydrogenase (ABAD). A selective and sensitive method for the presence of three new benzothiazole ABAD inhibitors in mouse plasma, brain, and artificial cerebrospinal fluid has been developed and validated based on high performance liquid chromatography tandem mass spectrometry. Mass spectra were generated using Micromass Quattro Ultima “triple” quadrupole mass spectrometer equipped with an Electrospray Ionization interface. Good linearity …was obtained over a concentration range of 0.05–2.5 μg/ml. The lowest limit of quantification and detection was found to be 0.05 μg/ml. All inter-day accuracies and precisions were within ± 15% of the nominal value and ± 20%, respectively, at the lower limit of quantitation. The tested compounds were stable at various conditions with recoveries >90.0% (RSD <10%). The method used for pharmacokinetic studies of compounds in mouse cerebrospinal fluid, plasma, and brain is accurate, precise, and specific with no matrix effect. Pharmacokinetic data showed that these compounds penetrate the blood-brain barrier (BBB) yielding 4–50 ng/ml peak brain concentrations and 2 μg/ml peak plasma concentrations from a 10 mg/kg dose. These results indicate that our newly synthesized small molecule ABAD inhibitors have a good drug properties with the ability to cross the blood-brain barrier, which holds a great potential for AD therapy. Show more

Keywords: ABAD inhibitors, amyloid-β, benzothiazole phosphonates, blood-brain barrier, pharmacokinetics

DOI: 10.3233/JAD-140252

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 333-344, 2014

Article Type: Other

DOI: 10.3233/JAD-140253

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 345-346, 2014