Journal of Alzheimer's Disease - Volume 44, issue 3

Authors: Morbelli, Silvia | Brugnolo, Andrea | Bossert, Irene | Buschiazzo, Ambra | Frisoni, Giovanni B. | Galluzzi, Samantha | van Berckel, Bart N.M. | Ossenkoppele, Rik | Perneczky, Robert | Drzezga, Alexander | Didic, Mira | Guedj, Eric | Sambuceti, Gianmario | Bottoni, Gianluca | Arnaldi, Dario | Picco, Agnese | De Carli, Fabrizio | Pagani, Marco | Nobili, Flavio

Article Type: Research Article

Abstract: We aimed to investigate the accuracy of FDG-PET to detect the Alzheimer's disease (AD) brain glucose hypometabolic pattern in 142 patients with amnestic mild cognitive impairment (aMCI) and 109 healthy controls. aMCI patients were followed for at least two years or until conversion to dementia. Images were evaluated by means of visual read by either moderately-skilled or expert readers, and by means of a summary metric of AD-like hypometabolism (PALZ score). Seventy-seven patients converted to AD-dementia after 28.6 ± 19.3 months of follow-up. Expert reading was the most accurate tool to detect these MCI converters from healthy controls (sensitivity 89.6%, …specificity 89.0%, accuracy 89.2%) while two moderately-skilled readers were less (p < 0.05) specific (sensitivity 85.7%, specificity 79.8%, accuracy 82.3%) and PALZ score was less (p < 0.001) sensitive (sensitivity 62.3%, specificity 91.7%, accuracy 79.6%). Among the remaining 67 aMCI patients, 50 were confirmed as aMCI after an average of 42.3 months, 12 developed other dementia, and 3 reverted to normalcy. In 30/50 persistent MCI patients, the expert recognized the AD hypometabolic pattern. In 13/50 aMCI, both the expert and PALZ score were negative while in 7/50, only the PALZ score was positive due to sparse hypometabolic clusters mainly in frontal lobes. Visual FDG-PET reads by an expert is the most accurate method but an automated, validated system may be particularly helpful to moderately-skilled readers because of high specificity, and should be mandatory when even a moderately-skilled reader is unavailable. Show more

Keywords: Alzheimer's disease, amnestic mild cognitive impairment, FDG-PET, PALZ score, visual read

DOI: 10.3233/JAD-142229

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 815-826, 2015

Authors: Acquaah-Mensah, George K. | Agu, Nnenna | Khan, Tayyiba | Gardner, Alice

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the leading cause of dementia. The etiology of AD remains, in large part, unresolved. In this study, gene expression (microarray) data from postmortem brains in normal aged as well as AD-affected brains in conjunction with transcriptional regulatory networks were explored for etiological insights. The focus was on the hippocampus, a brain region key to memory and learning. The transcriptional regulatory networks were inferred using a trees-based (random forests or extra-trees) as well as a mutual information-based algorithm applied to compendia of adult mouse whole brain and hippocampus microarray data. Network nodes representing human orthologs of the …mouse networks were used in the subsequent analysis. Among the potential transcriptional regulators tied to insulin or brain-derived neurotrophic factor (INS1, INS2, BDNF), whose peptide products have been linked to AD, is the Retinoic Acid Receptor-Related Orphan Receptor (RORA). RORA is a nuclear receptor transcription factor whose expression is distinctly upregulated in the AD hippocampus. A notable cross-section of genes differentially expressed in the AD hippocampus was found to be linked to RORA in the networks. Furthermore, several genes associated with RORA in the networks, such as APP, DNM1L, and TIA1 have been implicated in AD. Computationally-derived clusters and modules within the networks indicated strong ties between RORA and genes involved in the AD etiology. In addition, a functional mapping scheme using activity and interaction data affirmed the same network links to RORA. Thus, RORA emerges as a gene with a probable central role in the AD pathology/etiology. Show more

Keywords: Alzheimer's disease, retinoids, RORA, transcriptional networks

DOI: 10.3233/JAD-141731

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 827-838, 2015

Authors: Huang, Chunxia | Ho, Yuen-Shan | Ng, Olivia Tsz-Wa | Irwin, Michael G. | Chang, Raymond Chuen-Chung | Wong, Gordon Tin-Chun

Article Type: Research Article

Abstract: Exposure to anesthetic agents has been linked to abnormal tau protein phosphorylation, an antecedent to the development of neurofibrillary tangles. This study evaluates the direct and indirect effects of dexmedetomidine. Primary culture of cortical neurons established from Sprague-Dawley (SD) rat embryos were exposed to dexmedetomidine for 1 or 6 hours, and the degree of tau phosphorylation at the AT8, AT180, and S396 sites was assessed by western blot analysis. To assess and compare their relative in vivo effects, the same agent was administered intravenously to 8 to 10 week old male SD rats and titrated to the loss of the …righting reflex for 2 hours. After 1 hour of recovery, the rats were sacrificed and samples taken from the cortex and hippocampus were subjected to western blot and immunohistochemical analysis. The in vitro studies reviewed significant hyperphosphorylation only at the S396 site, and these changes have largely disappeared at 6 hours. With temperature maintenance, dexmedetomidine induced significant changes in hyperphosphorylation at the AT8 site in the cortex and hippocampus and at the AT180 in the hippocampus. The direct effect of anesthetic agents on fully differentiated cortical neurons is epitope-specific and short-lived. The in vivo effects are comparatively more complicated and depend not only on the phosphorylation site but the regions of the brain examined. These findings suggest that dexmedetomidine increases tau phosphorylation both in vitro and in vivo under normothermic conditions, and further studies are warranted to determine the long-term impact of this anesthetic on the tau pathology and even cognitive function. Show more

Keywords: Anesthetics, dexmedetomidine, hypothermia, protein kinases, tau phosphorylation

DOI: 10.3233/JAD-142238

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 839-850, 2015

Authors: Graham, Stewart F. | Nasarauddin, Muhammad Bin | Carey, Manus | McGuinness, Bernadette | Holscher, Christian | Kehoe, Patrick G. | Love, Seth | Passmore, Anthony P. | Elliott, Christopher T. | Meharg, Andrew | Green, Brian D.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is associated with significant disturbances in the homeostasis of Na+ and K+ ions as well as reduced levels of Na+/K+ ATPase in the brain. This study used ICP-MS to accurately quantify Na+ and K+ concentrations in human postmortem brain tissue. We analyzed parietal cortex (Brodmann area 7) from 28 cognitively normal age-matched controls, 15 cases of moderate AD, 30 severe AD, and 15 dementia with Lewy bodies (DLB). Associations were investigated between [Na+] and [K+] and a number of variables including diagnosis, age, gender, Braak tangle stage, amyloid-β (Aβ) plaque load, tau load, frontal tissue pH, and …APOE genotype. Brains from patients with severe AD had significantly higher (26%; p < 0.001) [Na+] (mean 65.43 ± standard error 2.91 mmol/kg) than controls, but the concentration was not significantly altered in moderate AD or DLB. [Na+] correlated positively with Braak stage (r = 0.45; p < 0.0001), indicating association with disease severity. [K+] in tissue was 10% lower (p < 0.05) in moderate AD than controls. However, [K+] in severe AD and DLB (40.97 ± 1.31 mmol/kg) was not significantly different from controls. There was a significant positive correlation between [K+] and Aβ plaque load (r = 0.46; p = 0.035), and frontal tissue pH (r = 0.35; p = 0.008). [Na+] was not associated with [K+] across the groups, and neither ion was associated with tau load or APOE genotype. We have demonstrated disturbances of both [Na+] and [K+] in relation to the severity of AD and markers of AD pathology, although it is possible that these relate to late-stage secondary manifestations of the disease pathology. Show more

Keywords: Alzheimer's disease, dementia with Lewy bodies, human brain, ICP-MS, potassium, sodium

DOI: 10.3233/JAD-141869

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 851-857, 2015

Authors: Al-khateeb, Eman | Althaher, Arwa | Al-khateeb, Mohammed | Al-Musawi, Hanan | Azzouqah, Ola | Al-Shweiki, Samir | Shafagoj, Yanal

Article Type: Research Article

Abstract: Background: It has been suggested that oxidative injuries have a role in the pathogenesis of Alzheimer's disease (AD). Uric acid (UA) has a contradictory effect on cognitive function and several lines of evidence suggest that UA may modulate outcome in neurological diseases. Objectives: Many studies investigated serum UA levels in AD patients, but to date, results from these observational studies are conflicting. In this study, we assess whether serum UA levels would be altered in the AD Jordanian patients compared to those of the healthy controls. Methods: Serum UA and lipid profile levels were measured in …41 AD patients and 40 healthy controls. Results were statistically evaluated at p < 0.05 level of significance. The Arabic version of the Mini-Mental State Examination (MMSE-A) was used to evaluate the cognitive functions of all participants. Results: Demographic variables indicate that individuals that are illiterate demonstrate a 7.5 fold (p = 0.033) increase in risk of developing AD. The AD group shows 12.6% lower serum UA level than control subjects and the difference between groups is statistically significant (p = 0.033). No significant differences could be found between the two groups in lipid profile levels. Pearson correlation coefficients and Multivarient linear regression show no significant correlation between MMSE and continuous variables in AD patients except for age. Conclusion: The results suggest that serum UA levels are significantly lower in AD patients in comparison to control subjects. UA may have a protective role against AD; however this role needs further investigations. Show more

Keywords: Aging, Alzheimer's disease, biomarkers, cholesterol, dementia, lipid profile, uric acid

DOI: 10.3233/JAD-142037

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 859-865, 2015

Authors: Hawkins, Kara M. | Goyal, Aman I. | Sergio, Lauren E.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is typically associated with impairments in memory and other aspects of cognition, while deficits in complex movements are commonly observed later in the course of the disease. Recent studies, however, have indicated that subtle deteriorations in visuomotor control under cognitively demanding conditions may in fact be an early identifying feature of AD. Our previous work has shown that the ability to perform visuomotor tasks that rely on visual-spatial and rule-based transformations is disrupted in prodromal and preclinical AD. Here, in a sample of 30 female participants (10 young: mean age = 26.6 ± 2.7, 10 low AD …risk: mean age = 58.7 ± 5.6, and 10 high AD risk: mean age = 58.5 ± 6.9), we test the hypothesis that these cognitive-motor impairments are associated with early AD-related brain alterations. Using diffusion-weighted magnetic resonance imaging, we examined changes in white matter (WM) integrity associated with normal aging and increased AD risk, and assessed the relationship between these underlying WM alterations and cognitive-motor performance. Our whole-brain analysis revealed significant age-related declines in WM integrity, which were more widespread in high relative to low AD risk participants. Furthermore, analysis of mean diffusivity measures within isolated WM clusters revealed a stepwise decline in WM integrity across young, low AD risk, and high AD risk groups. In support of our hypothesis, we also observed that lower WM integrity was associated with poorer cognitive-motor performance. These results are the first to demonstrate a relationship between AD-related WM alterations and impaired cognitive-motor control. The application of these findings may provide a novel clinical strategy for the early detection of individuals at increased AD risk. Show more

Keywords: Aging, Alzheimer's disease, diffusion tensor imaging, geriatric assessment, magnetic resonance imaging, motor skills, movement, neurodegenerative disorder

DOI: 10.3233/JAD-142079

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 867-878, 2015

Authors: Renziehausen, Jana | Hiebel, Christof | Nagel, Heike | Kundu, Arpita | Kins, Stefan | Kögel, Donat | Behl, Christian | Hajieva, Parvana

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the major age-associated form of dementia characterized by gradual cognitive decline. Aberrant cleavage of the amyloid-β protein precursor (AβPP) is thought to play an important role in the pathology of this disease. Two principal AβPP processing pathways exist: amyloidogenic cleavage of AβPP resulting in production of the soluble N-terminal fragment sAβPPβ, amyloid-β (Aβ), which accumulates in AD brain, and the AβPP intracellular domain (AICD) sAβPPα, p3 and AICD are generated in the non-amyloidogenic pathway. Prevalence of amyloidogenic versus non-amyloidogenic processing leads to depletion of sAβPPα and an increase in Aβ. Although sAβPPα is a well-accepted neurotrophic …protein, molecular effects of this fragment remains unknown. Different studies reported impaired protein degradation pathways in AD brain, pointing to a role of disturbed proteasomal activity in the pathogenesis of this disease. Here we studied the possible role of sAβPPα in Bag3-mediated selective macroautophagy and proteasomal degradation. Employing human IMR90 cells, HEK 293 cells, and primary neurons, we demonstrate that sAβPPα prevents the proteotoxic stress-induced increase of Bag3 at the protein and at the mRNA level indicating a transcriptional regulation. Intriguingly, p62 and LC3, two other key players of autophagy, were not affected. Moreover, the formation and the accumulation of disease-related protein aggregates were significantly reduced by sAβPPα. Interestingly, there was a significant increase of proteasomal activity by sAβPPα as demonstrated by using various proteasome substrates. Our findings demonstrate that sAβPPα modulates Bag3 expression, aggresome formation, and proteasomal activity, thereby providing first evidence for a function of sAβPPα in the regulation of proteostasis. Show more

Keywords: Alzheimer's disease, autophagy, Bag3 protein, fibroblasts, proteasome, sAβPPα

DOI: 10.3233/JAD-140600

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 879-896, 2015

Authors: Claxton, Amy | Baker, Laura D. | Hanson, Angela | Trittschuh, Emily H. | Cholerton, Brenna | Morgan, Amy | Callaghan, Maureen | Arbuckle, Matthew | Behl, Colin | Craft, Suzanne

Article Type: Research Article

Abstract: Previous trials have shown promising effects of intranasally administered insulin for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). These trials used regular insulin, which has a shorter half-life compared to long-lasting insulin analogues such as insulin detemir. The current trial examined whether intranasal insulin detemir improves cognition or daily functioning for adults with MCI or AD. Sixty adults diagnosed with MCI or mild to moderate AD received placebo (n = 20), 20 IU of insulin detemir (n = 21), or 40 IU of insulin detemir (n = 19) for 21 days, administered with a nasal …drug delivery device. Results revealed a treatment effect for the memory composite for the 40 IU group compared with placebo (p < 0.05). This effect was moderated by APOE status (p < 0.05), reflecting improvement for APOE-ε4 carriers (p < 0.02), and worsening for non-carriers (p < 0.02). Higher insulin resistance at baseline predicted greater improvement with the 40 IU dose (r = 0.54, p < 0.02). Significant treatment effects were also apparent for verbal working memory (p < 0.03) and visuospatial working memory (p < 0.04), reflecting improvement for subjects who received the high dose of intranasal insulin detemir. No significant differences were found for daily functioning or executive functioning. In conclusion, daily treatment with 40 IU insulin detemir modulated cognition for adults with AD or MCI, with APOE-related differences in treatment response for the primary memory composite. Future research is needed to examine the mechanistic basis of APOE-related treatment differences, and to further assess the efficacy and safety of intranasal insulin detemir. Show more

Keywords: Alzheimer's disease, clinical trials, randomized, insulin, intranasal drug administration, mild cognitive impairment

DOI: 10.3233/JAD-141791

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 897-906, 2015

Authors: Dauphinot, Virginie | Delphin-Combe, Floriane | Mouchoux, Christelle | Dorey, Aline | Bathsavanis, Anthony | Makaroff, Zaza | Rouch, Isabelle | Krolak-Salmon, Pierre

Article Type: Research Article

Abstract: Background: Caregivers play a major role in the care of patients with dementia and are themselves at higher risk of disease. Objectives: We investigate which factors are associated with caregivers burden of outpatients visiting a memory clinic and how functional autonomy and behavioral and psychological symptoms can influence caregiver burden. Methods: The study population was chosen from outpatients with progressive cognitive complaint. The caregiver burden was measured with the short version of the Zarit Burden Interview (ZBI). The relationship was assessed between the ZBI and the patients characteristics, including Neuropsychiatric Inventory (NPI), Instrumental Activities of Daily …Living scale (IADL), the Mini-Mental State Examination (MMSE), etiology, and stage of the cognitive impairment. Results: In a population of 548 patients, IADL, NPI, antidepressant drugs, and MMSE were found to be related to ZBI, while diagnosed etiology and disease stage were not significant: ZBI decreased by 0.34 point for every unit of IADL, and by 0.03 point for every unit of MMSE; ZBI increased by 0.03 point for every unit of NPI. From the IADL scale, the ability to handle finances, food preparation, responsibility to take medications, mode of transportation, and ability to use the telephone increased the ZBI. Five areas of the NPI increased the ZBI: apathy, agitation, aberrant motor behavior, appetite disorders (p < 0.001), and irritability (p = 0.03). Conclusion: Caregivers experience a higher burden due to disease symptoms such as impairment of functional autonomy and behavioral and cognitive impairment, whatever the etiology of the cognitive decline. Show more

Keywords: Alzheimer's disease or related disorder, behavioral disorders, caregiver, dementia, dependency, elderly

DOI: 10.3233/JAD-142337

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 907-916, 2015

Authors: Rembach, Alan | Stingo, Francesco C. | Peterson, Christine | Vannucci, Marina | Do, Kim-Anh | Wilson, William J. | Macaulay, S. Lance | Ryan, Timothy M. | Martins, Ralph N. | Ames, David | Masters, Colin L. | Doecke, James D. | the AIBL Research Group

Article Type: Research Article

Abstract: With different approaches to finding prognostic or diagnostic biomarkers for Alzheimer's disease (AD), many studies pursue only brief lists of biomarkers or disease specific pathways, potentially dismissing information from groups of correlated biomarkers. Using a novel Bayesian graphical network method, with data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, the aim of this study was to assess the biological connectivity between AD associated blood-based proteins. Briefly, three groups of protein markers (18, 37, and 48 proteins, respectively) were assessed for the posterior probability of biological connection both within and between clinical classifications. Clinical classification was defined …in four groups: high performance healthy controls (hpHC), healthy controls (HC), participants with mild cognitive impairment (MCI), and participants with AD. Using the smaller group of proteins, posterior probabilities of network similarity between clinical classifications were very high, indicating no difference in biological connections between groups. Increasing the number of proteins increased the capacity to separate both hpHC and HC apart from the AD group (0 for complete separation, 1 for complete similarity), with posterior probabilities shifting from 0.89 for the 18 protein group, through to 0.54 for the 37 protein group, and finally 0.28 for the 48 protein group. Using this approach, we identified beta-2 microglobulin (β2M) as a potential master regulator of multiple proteins across all classifications, demonstrating that this approach can be used across many data sets to identify novel insights into diseases like AD. Show more

Keywords: Alzheimer's disease, Bayesian, biomarkers, graphical networks, imputation

DOI: 10.3233/JAD-141497

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 917-925, 2015