Journal of Alzheimer's Disease - Volume 43, issue 3

Authors: Tryputsen, Volha | DiBernardo, Allitia | Samtani, Mahesh | Novak, Gerald P. | Narayan, Vaibhav A. | Raghavan, Nandini | the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Pittsburgh Compound B (PiB) positron emission tomography (PET) neuroimaging is a powerful research tool to characterize amyloid evolution in the brain. Quantification of amyloid load critically depends on (i) the choice of a reference region (RR) and (ii) on the selection of regions of interest (ROIs) to derive the standard uptake value ratios (SUVRs). Objective: To evaluate the stability, i.e., negligible amyloid accumulation over time, of different RRs, and the performance of different PiB summary measures defined by selected ROIs and RRs for their sensitivity to detecting longitudinal change in amyloid burden. Methods: To evaluate …RRs, cross-sectional and longitudinal analyses of focal regional and composite measures of amyloid accumulation were carried out on the standardized PiB-PET regional data for cerebellar grey matter (CER), subcortical white matter (SWM), and pons (PON). RRs and candidate composite SUVR measures were further evaluated to select regions and develop novel composites, using standardized 2-year change from baseline. Results: Longitudinal trajectories of PiB4—average of anterior cingulate (ACG), frontal cortex (FRC), parietal cortex, and precuneus—demonstrated marked variability and small change from baseline when normalized to CER, larger changes and less variability when normalized to SWM, which was further enhanced for the composite in PON-normalized settings. Novel composite PiB3, comprised of the average SUVRs of lateral temporal cortex, ACG, and FRC was created. Conclusion: PON and SWM appeared to be more stable RRs than the CER. PiB3 showed compelling sample size reduction and gains in power calculations for clinical trials over conventional PiB4 composite. Show more

Keywords: Alzheimer's disease, amyloid imaging, brain, pons, 11C-PiB

DOI: 10.3233/JAD-131979

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 809-821, 2015

Authors: Graybeal, John J. | Bozzelli, P. Lorenzo | Graybeal, Lacey L. | Groeber, Caitlin M. | McKnight, Patrick E. | Cox, Daniel N. | Flinn, Jane M.

Article Type: Research Article

Abstract: Disruptions to daily living, inflammation, and astrogliosis are characteristics of Alzheimer's disease. Thus, circadian rhythms, nest construction, IL-1β and TNF-α, and glial fibrillary acidic protein (GFAP) were examined in a mouse model developed to model late-onset Alzheimer's disease—the most common form of the disease. Mice carrying both the mutated human AβPP transgene found in the CRND8 mouse and the human apolipoprotein E ε4 allele (CRND8/E4) were compared with CRND8 mice and wildtype (WT) mice. Circadian rhythms were evaluated by wheel-running behavior. Activity of daily living was measured by nest construction. This study then examined mRNA levels of the inflammatory cytokines …IL-1β and TNF-α as well as protein levels of GFAP. Behavioral outcomes were then correlated with cytokines and GFAP. Compared to WT controls, both CRND8 and CRND8/E4 mice showed significantly more frequent, but shorter, bouts of activity. In the three groups, the CRND8/E4 mice had intermediate disruptions in circadian rhythms. Both CRND8/E4 mice and CRND8 mice showed significant impairments in nesting behavior compared to WTs. While CRND8 mice expressed significantly increased IL-1β and GFAP expression compared to WT controls, CRND8/E4 mice expressed intermediate IL-1β and GFAP levels. Significant correlations between IL-1β, GFAP, and behavior were observed. These data are congruent with other studies showing that human ApoE ε4 is protective early in life in transgenic mice modeling Alzheimer's disease. Show more

Keywords: Alzheimer's disease, apolipoprotein E4, circadian rhythm, cytokines, glial fibrillary acidic protein, gliosis, IL-1β, nesting behavior, TNF-α, transgenic mice

DOI: 10.3233/JAD-132009

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 823-834, 2015

Authors: Ivanoiu, Adrian | Dricot, Laurence | Gilis, Nathalie | Grandin, Cécile | Lhommel, Renaud | Quenon, Lisa | Hanseeuw, Bernard

Article Type: Research Article

Abstract: Background: New diagnostic criteria for predemential Alzheimer's disease (AD) advocate the use of biomarkers. However, the benefit of using biomarkers has not been clearly demonstrated in clinical practice. Objective: To investigate whether a combination of biomarkers may be helpful in classifying a population of non-demented patients attending a Memory Clinic. Methods: Sixty non-demented patients were compared with 31 healthy elderly subjects. All subjects underwent a neuropsychological examination, brain 3T magnetic resonance imaging, [F18]-fluorodeoxyglucose and [F18]-flutemetamol positron emission tomography. According to their performance on memory, language, executive, and visuo-spatial domains, the patients were classified as mild cognitive …impairment (amnestic, non-amnestic, single, or multiple domain) or subjective cognitive impairment. Patients were then classified according to the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria, using the normalized mean hippocampal volume (Freesurfer), [F18]-FDG PALZAD, and [F18]-flutemetamol standard uptake value ratio (SUVr) (cut-off at the 10th percentile of controls). The standard of truth was the clinical status at study entry (patient versus control). Results: The sensitivity/specificity of the clinical classification was 65/84%. The NIA-AA criteria were applicable in 85% of patients and 87% of controls. For biomarkers the best sensitivity (72%) at a fixed specificity of 84% was achieved by a combination of the three biomarkers. The clinical diagnosis was reconsidered in more than one third of the patients (42%) as a result of including the biomarker results. Conclusions: Application of the new NIA-AA AD diagnostic criteria based on biomarkers in an unselected sample of non-demented patients attending a Memory Clinic was useful in allowing for a better classification of the subjects. Show more

Keywords: Alzheimer's disease, biological markers, early diagnosis, mild cognitive impairment

DOI: 10.3233/JAD-140651

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 835-847, 2015

Authors: Grossi, Dario | de Lucia, Natascia | Trojano, Luigi

Article Type: Research Article

Abstract: Background: Apathy and depression are behavioral manifestations that may occur often in Alzheimer's disease (AD) patients. AD patients may also show Closing-in (CI) phenomenon, in graphic copying tasks. Recent evidence would suggest that apathetic symptoms are related to frontal dysfunctions in AD patients, whereas the cognitive bases of depressive symptoms in AD are still unclear. Recent studies demonstrated that frontal dysfunctions are also involved in the genesis of CI in AD patients. Objective: Since frontal dysfunctions are thought to be more strongly related to apathetic than depressive symptoms, here we tested the hypothesis that CI is significantly associated …with apathy in AD patients. Methods: Forty-four AD patients were enrolled for this study. All patients completed a neuropsychological evaluation of visuo-spatial, frontal/executive, visuo-constructional, and memory skills. Moreover, graphic copying tasks were employed to detect CI, and behavioral scales to assess apathetic and depressive symptoms. Results: CI and apathetic and depressed symptoms occurred in more than half of the present AD sample, but regression models revealed that the number of CI was significantly related to apathy only. The number of CI was also significantly correlated with severity of apathetic but not of depressive symptoms. Conclusion: The present study demonstrated that CI and apathy are correlated with each other in mild to moderate AD, likely because they share common pathogenic mechanisms related to frontal/executive dysfunctions. Show more

Keywords: Alzheimer's disease, apathy, closing-in, depression, frontal defect

DOI: 10.3233/JAD-141257

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 849-855, 2015

Authors: Fu, YuHong | Hsiao, Jen-Hsiang T. | Paxinos, George | Halliday, Glenda M. | Kim, Woojin Scott

Article Type: Research Article

Abstract: Brain cholesterol homeostasis is regulated by a group of proteins called ATP-binding cassette subfamily A (ABCA) transporters. Certain ABCA transporters regulate amyloid-β protein precursor (AβPP) processing to generate amyloid-β peptides (Aβ) and are associated with an increased risk for late-onset Alzheimer's disease (AD). ABCA5 is a little-known member of the ABCA subfamily with no known function. In this study we undertook a comprehensive analysis of ABCA5 expression in the human and mouse brains. We explored the potential role of ABCA5 in AβPP processing associated with AD pathology. ABCA5 was differentially expressed in multiple regions of both human and mouse brains. …It was strongly expressed in neurons with only weak expression in microglia, astrocytes, and oligodendrocytes. ABCA5 was able to stimulate cholesterol efflux in neurons. ABCA5 expression was specifically elevated in the hippocampus of AD brains. Using two in vitro cell systems we demonstrated that ABCA5 reduces Aβ production, both Aβ40 and Aβ42 , without altering AβPP mRNA and protein levels, indicating that the decrease in the Aβ levels was due to changes in AβPP processing and not AβPP expression. This report represents the first extensive expression and functional study of ABCA5 in the human brain and our data suggest a plausible function of ABCA5 in the brain as a cholesterol transporter associated with Aβ generation, information that may offer a potential new target for controlling Aβ levels in the brain. Show more

Keywords: ABC transporter, Alzheimer's disease, amyloid-β peptide, amyloid-β protein precursor, neurodegeneration, neuron

DOI: 10.3233/JAD-141320

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 857-869, 2015

Authors: Dekker, Alain D. | Coppus, Antonia M.W. | Vermeiren, Yannick | Aerts, Tony | van Duijn, Cornelia M. | Kremer, Berry P. | Naudé, Pieter J.W. | Van Dam, Debby | De Deyn, Peter P.

Article Type: Research Article

Abstract: Background: Down syndrome (DS) is the most prevalent genetic cause of intellectual disability. Early-onset Alzheimer's disease (AD) frequently develops in DS and is characterized by progressive memory loss and behavioral and psychological signs and symptoms of dementia (BPSD). Predicting and monitoring the progression of AD in DS is necessary to enable adaptive caretaking. Objective: Reliable blood biomarkers that aid the prediction of AD are necessary, since cerebrospinal fluid sampling is rather burdensome, particularly for people with DS. Here, we investigate serum levels of eight biogenic amines and their metabolites in relation to dementia staging and probable BPSD items. …Methods: Using RP-HPLC with electrochemical detection, (nor)adrenergic (NA/A and MHPG), serotonergic (5-HT and 5-HIAA), and dopaminergic (DA, HVA, and DOPAC) compounds were quantified in the serum of DS subjects with established AD at baseline (n = 51), DS subjects without AD (n = 50), non-demented DS individuals that converted to AD over time (n = 50), and, finally, healthy non-DS controls (n = 22). Results: Serum MHPG levels were significantly lower in demented and converted DS subjects (p < 0.0001) compared to non-demented DS individuals and healthy controls. Those subjects with MHPG levels below median had a more than tenfold increased risk of developing dementia. Furthermore, significant correlations were observed between monoaminergic serum values and various probable BPSD items within each DS group. Conclusion: Decreased serum MHPG levels show great potential as biomarker to monitor and predict conversion to AD in DS. Moreover, significant monoaminergic alterations related to probable BPSD items, suggesting that monoaminergic dysregulation is an underlying biological mechanism, and demonstrating the need to develop a validated rating scale for BPSD in DS. Show more

Keywords: Alzheimer's disease, behavioral and psychological signs and symptoms of dementia (BPSD), biogenic amines, biomarkers, Down syndrome, MHPG, RP-HPLC

DOI: 10.3233/JAD-140783

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 871-891, 2015

Authors: Dunn, Haley C. | Ager, Rahasson R. | Baglietto-Vargas, David | Cheng, David | Kitazawa, Masashi | Cribbs, David H. | Medeiros, Rodrigo

Article Type: Research Article

Abstract: The initiation of an inflammatory response is critical to the survival of an organism. However, when inflammation fails to reach resolution, a chronic inflammatory state may occur, potentially leading to bystander tissue damage. Accumulating evidence suggests that chronic inflammation contributes to the progression of Alzheimer's disease (AD), and identifying mechanisms to resolve the pro-inflammatory environment stimulated by AD pathology remains an area of active investigation. Previously, we found that treatment with the pro-resolving mediator aspirin-triggered lipoxin A4 (ATL), improved cognition, reduced Aβ levels, and enhanced microglia phagocytic activity in Tg2576 transgenic AD mice. Here, we evaluated the effect of …aging on brain lipoxin A4 (LXA4 ) levels using non-transgenic and 3xTg-AD mice. Additionally, we investigated the effect of ATL treatment on tau pathology in 3xTg-AD mice. We found that LXA4 levels are reduced with age, a pattern significantly more impacted in 3xTg-AD mice. Moreover, ATL delivery enhanced the cognitive performance of 3xTg-AD mice and reduced Aβ levels, as well as decreased the levels of phosphorylated-tau (p-tau). The decrease in p-tau was due in part to an inhibition of the tau kinases GSK-3β and p38 MAPK. In addition, microglial and astrocyte reactivity was inhibited by ATL treatment. Our results suggest that the inability to resolve the immune response during aging might be an important feature that contributes to AD pathology and cognitive deficits. Furthermore, we demonstrate that activation of LXA4 signaling could serve as a potential therapeutic target for AD-related inflammation and cognitive dysfunction. Show more

Keywords: Aging, Alzheimer's disease, aspirin-triggered lipoxin A4, inflammation, lipoxin, lipoxygenase, resolution, 3xTg-AD

DOI: 10.3233/JAD-141335

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 893-903, 2015

Authors: Sousa, Maria Fernanda B. | Santos, Raquel L. | Nogueira, Marcela L. | Belfort, Tatiana | Rosa, Rachel D.L. | Torres, Bianca | Simões, Pedro | Mograbi, Daniel C. | Laks, Jerson | Dourado, Marcia C.N.

Article Type: Research Article

Abstract: Awareness of disease can be compromised to some degree in a proportion of people with dementia, with evident differences across domains. We designed this study to determine the factors associated with the impairment of awareness over a period of time. Using a longitudinal design, 69 people with mild Alzheimer's disease and their family caregivers completed the Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia, the Quality of Life in Alzheimer's Disease Scale, the Mini-Mental State Examination, the Clinical Dementia Rating Scale, the Cornell Scale for Depression in Dementia, the Pfeffer Functional Activities Questionnaire, the Neuropsychiatric Inventory, and the …Zarit Burden Interview. Univariate and logistic regression analyses were conducted to examine the contribution of the various factors. The level of awareness of disease was significantly lower (p ≤ 0.001) between baseline and at follow up. At follow up, there was no change in the level of awareness of disease in 61.8%, whereas 25.4% worsened. However, the level of awareness improved in 12.3%. Logistic regression demonstrated that functional deficits (OR = 1.12, 95% CI: (1.03–1.22), p ≤ 0.01), and caregivers' quality of life (OR = 0.83, 95% CI: (0.70–0.98), p ≤ 0.05) were a significant predictor of impaired awareness of disease. The results confirmed that awareness and cognition are relatively independent, and showed that in people with mild dementia, unawareness is mainly manifested by poor recognition of changes in the activities of daily living, and decrease in quality of life. Show more

Keywords: Activities of daily living, Alzheimer's disease, anosognosia, awareness, dementia, longitudinal studies, quality of life

DOI: 10.3233/JAD-140342

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 905-913, 2015

Authors: Paholikova, Kristina | Salingova, Barbara | Opattova, Alena | Skrabana, Rostislav | Majerova, Petra | Zilka, Norbert | Kovacech, Branislav | Zilkova, Monika | Barath, Peter | Novak, Michal

Article Type: Research Article

Abstract: Tau protein is a member of microtubule-associated protein family. Under pathological conditions, tau undergoes multiple modifications that lead to the formation of insoluble deposits in neurons, resulting in neuronal dysfunction in several neurodegenerative disorders collectively called tauopathies, with Alzheimer's disease being the most frequent example. This typical cytosolic protein has been shown to translocate into the nucleus and participate in DNA protection upon stress conditions. In our study, we demonstrate that truncated Tau151-391/4R changes its usual behavior and gains constitutive access into the nucleus of both primary rat neurons and human neuroblastoma cells. Our results show that partial/dysregulated nuclear localization …of tau results from the removal of the N-terminal (1–150) residues of the protein. Data obtained by cell fractionation data were supported by confocal microscopy analysis of GFP-fused tau proteins. Furthermore, neither addition of the fusion protein, nor increased tau phosphorylation had any effect on the intracellular distribution of truncated tau. Our data further suggest that differential tau phospho-status between cytosolic and nuclear fractions is rather a consequence than a cause of truncated tau nuclear localization. Finally, truncated tau in the nucleus is engaged in interactions with subnuclear structure(s), since it exhibits reduced mobility. We conclude that N-terminal truncation of tau proteins leads to their nonphysiological subcellular distribution as a result of modified tau conformation. Show more

Keywords: Alzheimer's disease, cell compartmentation, cell nucleus, neurodegenerative diseases, tau proteins, truncation

DOI: 10.3233/JAD-140996

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 915-926, 2015

Authors: Hagl, Stephanie | Grewal, Rekha | Ciobanu, Ion | Helal, Amr | Khayyal, Mohamed T. | Muller, Walter E. | Eckert, Gunter P.

Article Type: Research Article

Abstract: Mitochondrial dysfunction plays an important role in brain aging and has emerged to be an early event in Alzheimer's disease (AD), contributing to neurodegeneration and the loss of physical abilities seen in patients suffering from this disease. We examined mitochondrial dysfunction in a cell culture model of AD (PC12APPsw cells) releasing very low amyloid-β (Aβ40 ) levels and thus mimicking early AD stages. Our data show that these cells have impaired energy metabolism, low ATP levels, and decreased endogenous mitochondrial respiration. Furthermore, protein levels of PGC1α as well as of Mitofusin 1 were decreased. PC12APPsw cells also showed …increased mitochondrial content, probably due to an attempt to compensate the impaired mitochondrial function. Recent data showed that stabilized rice bran extract (RBE) protects from mitochondrial dysfunction in vivo Pharmacol Res. (2013) 76C, 17–27. To assess the effect of RBE on mitochondrial function, we treated PC12APPsw cells for 24 h with RBE. Key components of RBE are oryzanols, tocopherols, and tocotrienols, all substances that have been found to exert beneficial effects on mitochondrial function. RBE incubation elevated ATP production and respiratory rates as well as PGC1α protein levels in PC12APPsw cells, thus improving the impaired mitochondrial function assessed in our cell culture AD model. Therefore, RBE represents to be a promising nutraceutical for the prevention of AD. Show more

Keywords: Alzheimer's disease, bioenergetics, mitochondria, mitochondrial dynamics, nitrosative stress, nutrition, PC12 cells, respiration, rice bran extract

DOI: 10.3233/JAD-132084

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 927-938, 2015