Journal of Alzheimer's Disease - Volume 64, issue 4

Authors: Liu, Ning | Yu, Zhanyang | Xun, Yu | Shu, Pan | Yue, Yiwei | Yuan, Shishan | Jiang, Yinghua | Huang, Zixuan | Yang, Xiaoping | Feng, Xing | Xiang, Shuanglin | Wang, Xiaoying

Article Type: Research Article

Abstract: Neuroglobin (Ngb) has been reported to be increased in early and moderately advanced Alzheimer’s disease (AD) stages but declined in the severe stage. However, its regulatory mechanisms and pathophysiological roles in the disease remain to be defined. In this study, we found that Ngb expression was significantly upregulated by low dose Aβ25–35 , the neurotoxic fragment of Aβ1 - 40 and Aβ1 - 42 , but was not further increased by a higher dose of Aβ25–35 . Mutation analysis and supershift assay demonstrated that transcription factor Nuclear Factor κ B (NFκ B), κ B2 and κ B3 sites located …in mouse Ngb promoter region were involved in dynamic regulation of Ngb expression in response to different doses of Aβ25–35 stimulation. In addition, we found that suppression of endogenous Ngb expression exacerbated Aβ25–35 -induced neuronal cell death and mitochondrial dysfunction. Our results indicate that endogenous Ngb expression may be upregulated by low dose Aβ25–35, which is responsible for protecting against Aβ25–35 -mediated neurotoxicity. These experimental findings suggest that upregulation of endogenous Ngb expression might be an effective intervention approach for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, mitochondria, neuroglobin, neurotoxicity, NFκB

DOI: 10.3233/JAD-180163

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1163-1174, 2018

Authors: Smailagic, Nadja | Lafortune, Louise | Kelly, Sarah | Hyde, Chris | Brayne, Carol

Article Type: Research Article

Abstract: Background: A previous Cochrane systematic review concluded there is insufficient evidence to support the routine use of 18 F-FDG PET in clinical practice in people with mild cognitive impairment (MCI). Objectives: To update the evidence and reassess the accuracy of 18 F-FDG-PET for detecting people with MCI at baseline who would clinically convert to Alzheimer’s disease (AD) dementia at follow-up. Methods: A systematic review including comprehensive search of electronic databases from January 2013 to July 2017, to update original searches (1999 to 2013). All key review steps, including quality assessment using QUADAS 2, were performed independently …and blindly by two review authors. Meta-analysis could not be conducted due to heterogeneity across studies. Results: When all included studies were examined across all semi-quantitative and quantitative metrics, exploratory analysis for conversion of MCI to AD dementia (n = 24) showed highly variable accuracy; half the studies failed to meet four or more of the seven sets of QUADAS 2 criteria. Variable accuracy for all metrics was also found across eleven newly included studies published in the last 5 years (range: sensitivity 56–100%, specificity 24–100%). The most consistently high sensitivity and specificity values (approximately ≥80%) were reported for the sc-SPM (single case statistical parametric mapping) metric in 6 out of 8 studies. Conclusion: Systematic and comprehensive assessment of studies of 18 FDG-PET for prediction of conversion from MCI to AD dementia reveals many studies have methodological limitations according to Cochrane diagnostic test accuracy gold standards, and shows accuracy remains highly variable, including in the most recent studies. There is some evidence, however, of higher and more consistent accuracy in studies using computer aided metrics, such as sc-SPM, in specialized clinical settings. Robust, methodologically sound prospective longitudinal cohort studies with long (≥5 years) follow-up, larger consecutive samples, and defined baseline threshold(s) are needed to test these promising results. Further evidence of the clinical validity and utility of 18 F-FDG PET in people with MCI is needed. Show more

Keywords: Accuracy, Alzheimer’s disease dementia, conversion, 18F-FDG PET, mild cognitive impairment, test predictive value

DOI: 10.3233/JAD-171125

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1175-1194, 2018

Authors: Lamartinière, Yordenca | Boucau, Marie-Christine | Dehouck, Lucie | Krohn, Markus | Pahnke, Jens | Candela, Pietra | Gosselet, Fabien | Fenart, Laurence

Article Type: Research Article

Abstract: The role of ABCA7 in brain homeostasis and Alzheimer’s disease (AD) is currently under intense scrutiny, since it has been reported that polymorphisms in the Abca7 gene and a loss of function of the protein are closely linked to excessive accumulation of amyloid peptides and disturbed cholesterol homeostasis. The blood-brain barrier (BBB), which isolates the brain from the blood compartment, is involved in both of these processes. We therefore hypothesized that ABCA7 downregulation might affect cholesterol and amyloid exchanges at the BBB. Using siRNA and primary cultures of mouse endothelial cells purified from brain microvessels and seeded on Transwell …® inserts, we investigated the role of ABCA7 in cholesterol and amyloid exchanges across the BBB. Our results showed that a decrease in ABCA7 expression at the BBB provokes in vitro a reduction in ABCA1 expression and a decrease in APOE secretion. In vitro , these decreases reduce cholesterol exchange across the BBB, particularly for high-density lipoproteins and ApoA-I particles. When ABCA7 was absent, we observed a reduction in Aβ peptide basolateral-to-apical transport in the presence of ApoA-I, with non-significant changes in the expression levels of Rage , Lrp1 , Abcb1 , Abcc1 , and Abcg2 . Our study in murine BBB model highlighted a putative new role for ABCA7 in AD via the protein’s involvement in cholesterol metabolism and amyloid clearance at the BBB. Show more

Keywords: ABCA7, Aβ peptides, Alzheimer’s disease, blood-brain barrier, cholesterol metabolism

DOI: 10.3233/JAD-170883

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1195-1211, 2018

Authors: Burgio, Francesca | Delazer, Margarete | Meneghello, Francesca | Pertl, Marie-Theres | Semenza, Carlo | Zamarian, Laura

Article Type: Research Article

Abstract: Background: Patients with mild cognitive impairment (MCI) show lower decision making and ratio processing abilities as compared to healthy peers. Objective: To evaluate whether cognitive training on number processing and/or executive functions improves performance on ratio processing and decision making under risk. Methods: In a controlled cross-over study, patients with MCI (n = 23; mean MMSE 26.48, SD 2.43) underwent a week of numerical training followed by a week of executive-functions training (subgroup A), or vice versa (subgroup B). Before training (T1), patients performed experimental tasks of decision making (Game of Dice Task, GDT; Probability-Associated …Gambling task, PAG-60 task) and of ratio processing as well as a neuropsychological background assessment. Experimental tasks were also administered after the first (T2) and the second (T3) training week. Results: The numerical training and the training of executive functions had a differential effect on experimental tasks of ratio processing. Only the numerical training proved to be effective. The effects of the two training types on decision making under risk were less clear-cut. While no changes over time were observed in the GDT, performance on the PAG-60 task improved in both training subgroups. These improvements were apparent in one subgroup after a period of executive-functions training, in the other subgroup after both training weeks. That means, improvements are not attributable to one specific training type. Conclusion: Patients with MCI can profit from a cognitive training on number processing and executive functions. Improvements are reflected in higher ratio processing abilities and more advantageous decisions after training. These results are consistent with assumptions of current cognitive models. Show more

Keywords: Executive functions, intervention, medical information, neuropsychology, numerical processing

DOI: 10.3233/JAD-180461

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1213-1226, 2018

Authors: Sahoo, Aradhana | Bejanin, Alexandre | Murray, Melissa E. | Tosakulwong, Nirubol | Weigand, Stephen D. | Serie, Amanda M. | Senjem, Matthew L. | Machulda, Mary M. | Parisi, Joseph E. | Boeve, Bradley F. | Knopman, David S. | Petersen, Ronald C. | Dickson, Dennis W. | Whitwell, Jennifer L. | Josephs, Keith A.

Article Type: Research Article

Abstract: Background: TDP-43 has been shown to be strongly associated with memory loss, smaller hippocampal volumes, and faster rates of hippocampal atrophy in Alzheimer’s disease (AD) patients with an amnestic presentation. Whether TDP-43 has any clinical or anatomical associations in AD patients with non-amnestic phenotype is unknown. Objective: To determine whether TDP-43 plays a significant role in the clinic-anatomic features of non-amnestic AD. Methods: All cases with pathologically confirmed intermediate-high probability AD from 1996–2012 were identified and retrospectively sub-classified into amnestic versus non-amnestic dementia at the time of presentation. Neurofibrillary tangle counts were performed in those with …a non-amnestic presentation using thioflavin-S microscopy in the hippocampus and three neocortical regions, and all cases were subtyped into hippocampal-sparing, limbic-predominant, and typical AD pathology. TDP-43 immunoreactivity was used to assess for the presence of TDP-43. Statistical analyses helped determine whether pathologic subtype or TDP-43 was more strongly associated with clinico-imaging features. Results: Out of 172 pathologically confirmed AD cases, 36 (19%) were classified as non-amnestic. Twenty-five of these 36 (69%) had typical pathology, 0 limbic-predominant pathology, and 11 (31%) hippocampal-sparing pathology. Eleven (44%) of the 25 cases with typical pathology were TDP-43+. Of the 11 cases with hippocampal-sparing pathology, 4 (36%) were TDP-43+. There were no differences in demographic, clinical, or neuroimaging features in those with TDP-43 versus those without except for older age at onset (p = 0.02) and age at death (p = 0.02) in those with TDP-43. AD pathological subtype accounted for slightly more of the variances in the neocortex than TDP-43. Conclusion: In non-amnestic AD, we find little evidence that clinical or anatomical features of the disease are related to TDP-43. Show more

Keywords: Alzheimer’s disease, atypical AD, non-amnestic, TDP-43

DOI: 10.3233/JAD-180169

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1227-1233, 2018

Authors: Chan, Parco | Saleem, Mahwesh | Herrmann, Nathan | Mielke, Michelle M. | Haughey, Norman J. | Oh, Paul I. | Kiss, Alexander | Lanctôt, Krista L.

Article Type: Research Article

Abstract: Background: Biomarkers in cognitively vulnerable populations, like those with coronary artery disease (CAD), may inform earlier intervention in vascular neurodegeneration. Circulating ceramide C18:0 (CerC18:0) is associated with changes in verbal memory in early neurodegeneration and CAD progression. Objective: To investigate whether plasma CerC18:0 accumulation is associated with longitudinal declines in verbal memory performance in CAD. Methods: In addition to total CerC18:0, we assessed its relative abundance to its precursors as ratios: CerC18:0 to monohexosylceramide C18:0 (MHxCer18:0), CerC18:0 to sphingomyelin C18:0 (SM18:0), and CerC18:0 to sphingosine-1-phosphate (S1P). Verbal memory was assessed using the California Verbal Learning Test …2nd Ed. Using mixed models in 60 CAD participants, we evaluated associations between baseline CerC18:0 ratios and changes in verbal memory performance, adjusting for age, body mass index, and education. Given that cognitive decline is more rapid following onset of deficits, these associations were compared between those with possible mild vascular neurocognitive disorder (MVND). Results: Increased baseline CerC18:0 concentrations correlated with worse verbal memory performance over time (b[SE] = – 0.91[0.30], p = 0.003). Increased baseline CerC18:0/SM18:0 (b [SE] = – 1.11[`], p = 0.03) were associated with worse verbal memory performance over time. These associations were not mediated by whether or not patients had possible MVND at baseline. Conclusion: These findings support aberrant CerC18:0 metabolism as an early neurobiological change in vascular neurodegeneration. Future studies should measure enzymes responsible for conversion of sphingolipid precursors into CerC18:0 to assess enzymatic activity. Show more

Keywords: Ceramides, coronary artery disease, cognition, memory, sphingolipids

DOI: 10.3233/JAD-180030

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1235-1246, 2018

Authors: Thygesen, Camilla | Metaxas, Athanasios | Larsen, Martin R. | Finsen, Bente

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), the most common cause of dementia, is characterized by the intra- and extracellular aggregation and accumulation of proteins. The major molecular hallmark is the aggregation of amyloid-β (Aβ ) and hyperphosphorylated tau proteins into plaques and tangles, respectively. Evidence points to the pre-fibrillary states of protein aggregates harboring the greatest neurotoxicity. Objective: This study was designed to identify and quantify pre-fibrillary protein species enriched by their insolubility in the detergent sarkosyl in the APPSWE /PS1ΔE9 (APP/PS1) transgenic mouse model of AD. Sarkosyl insoluble fractions were isolated from the brains of APP/PS1 and …littermate wild type (Wt) mice to identify pre-fibrillary protein species associated with AD. Methods: Pre-fibrillary protein species were isolated from the brains of 3- and 24-month-old APP/PS1 and littermate Wt mice using sarkosyl extraction and subjected to quantitative proteomics analysis by the use of isobaric tags for relative and absolute quantitation (iTRAQ). Results: The sarkosyl-insoluble pre-fibrillary proteome showed differential age- and genotype-induced effects. In addition to Aβ and tau, old APP/PS1 mice showed significant enrichment in proteins in the sarkosyl fraction involved in oxidative phosphorylation and mitochondrial function. Conclusion: The results of this study implicate dysfunctional mitochondria as playing a key role of Aβ - and potentially tau-induced pathological events in the APP/PS1 transgenic mouse model of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, APPSWE/PS1ΔE9, iTRAQ, mass spectrometry, oxidative stress, proteomics, tau

DOI: 10.3233/JAD-180197

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1247-1259, 2018

Authors: Shao, Yi | Jiang, Hong | Wei, Yantao | Shi, Yingying | Shi, Ce | Wright, Clinton B. | Sun, Xiaoyan | Vanner, Elizabeth A. | Rodriguez, Anny D. | Lam, Byron L. | Rundek, Tatjana | Baumel, Barry S. | Gameiro, Giovana Rosa | Dong, Chuanhui | Wang, Jianhua

Article Type: Research Article

Abstract: Background: A detailed analysis of the tomographic thickness of intraretinal layers may provide more information on neurodegeneration in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Objective: The goal was to analyze tomographic thickness patterns of intraretinal layers in patients with AD andMCI. Method: Forty-nine patients (25 AD and 24 MCI) and 21 cognitively normal (CN) controls were imaged using ultra-high-resolution optical coherence tomography to obtain volumetric data centered on the fovea. The segmented intraretinal layers were retinal nerve fiber layer (RNFL), ganglion cell– inner plexiform layer (GCIPL), inner nuclear layer (INL), outer nuclear …layer (ONL), outer plexiform layer (OPL), and retinal photoreceptor (PR), in addition to the total retinal thickness(TRT). Results: The thickness differences were negative (thinning) mainly in TRT, RNFL, and GCIPL in both AD and MCI groups in comparison to CN, while the thickness differences were positive (thickening) mainly in ONL and PR in AD. GCIPL of AD and MCI was thinner in superior, nasal superior, and temporal superior quadrants, compared to CN (p < 0.05). GCIPL of the inner superior, inner nasal superior, inner temporal superior, and outer nasal superior sectors was significantly thinner in AD than CN (p < 0.05). GCIPL of the outer superior, inner temporal superior, outer nasal, and temporal superior sectors was significantly thinner in MCI than CN (p < 0.05). Conclusion: Focal thinning of the GCIPL was visualized and quantified by detailed partitions in AD and MCI, which provides specific information about neurodegeneration in MCI and AD. Show more

Keywords: Alzheimer’s disease, ETDRS partition, ganglion-inner plexiform layer, hemispheric partition, mild cognitive impairment, retinal thickness mapping, ultrahigh-resolution OCT, Zeiss elliptical partition

DOI: 10.3233/JAD-180070

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1261-1273, 2018

Authors: Sao, Tomoko | Yoshino, Yuta | Yamazaki, Kiyohiro | Ozaki, Yuki | Mori, Yoko | Ochi, Shinichiro | Yoshida, Taku | Mori, Takaaki | Iga, Jun-Ichi | Ueno, Shu-Ichi

Article Type: Research Article

Abstract: Background: Triggering receptor expressed on myeloid cells 2 (TREM2) activates the innate immune system, promotes phagocytosis by microglia, and is associated with Alzheimer’s disease (AD). The possible role of a related molecule, TREM1, in AD remains unknown. Objective: We investigated a possible role for TREM1 in AD by determining the gene expression and methylation levels of TREM1 in leukocytes from AD patients. Methods: Fifty patients with AD and 50 age-matched healthy controls were enrolled. AD patients underwent a battery of neuropsychiatric tests. Peripheral blood samples were obtained from each participant, RNA and DNA were extracted, and …samples were assessed for TREM1 mRNA expression and methylation rates at three CpG sites in the TREM1 promoter. Results: TREM1 mRNA expression levels in AD patients were significantly higher than those in controls (p = 0.008). TREM1 mRNA expression levels were not correlated with sex, age, duration of illness, APOE genotype, donepezil treatment, or scores of most neuropsychiatric tests. TREM1 mRNA expression levels in AD patients were correlated with the total score of the Montgomery-Åsberg Depression Rating Scale (p = 0.047, r = – 0.344). Methylation rates at the three CpG sites were significantly lower in AD patients than in controls. We also found a significant correlation between TREM1 mRNA expression and TREM1 DNA methylation rates (p < 0.001). Conclusion: TREM1 may be associated with the immune responses in AD, and along with hypomethylation at CpG sites in the TREM1 promoter, may become part of a biomarker panel for AD pathogenesis. Show more

Keywords: Alzheimer’s disease, cognitive function, DNA methylation, gene expression, TREM1, TREM2

DOI: 10.3233/JAD-180418

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1275-1284, 2018

Authors: Bonnechère, Bruno | Van Vooren, Mélissa | Bier, Jean-Christophe | De Breucker, Sandra | Van Hove, Olivier | Van Sint Jan, Serge | Feipel, Véronique | Jansen, Bart

Article Type: Research Article

Abstract: Background: In the past few years numerous mobile games have been developed to train the brain. There is a lack of information about the relation between the scores obtained in these games and the cognitive abilities of the patients. Objective: The aim of this study was to determine whether or not mobile games can be used to assess cognitive abilities of elderly. Methods: Twenty healthy young adults, 29 old patients with cognitive impairments (Mini-Mental State Exam (MMSE) [20– 24 ]) and 27-aged controls participated in this study. Scores obtained in 7 mobile games were correlated with …MMSE and the Addenbrooke’s Cognitive Evaluation revised (ACE-R). Results: Statistically significant differences were found for all games between patients with cognitive impairments and the aged controls. Correlations between the average scores of the games and the MMSE and ACE-R are significant (R = 0.72 [p < 0.001] and R = 0.81 [p < 0.001], respectively). Conclusion: Scores of cognitive mobile games could be used as an alternative to MMSE and ACE-R to evaluate cognitive function of aged people with and without cognitive impairment at least when MMSE is higher than 20/30. Show more

Keywords: Assessment, cognitive evaluation, dementia, mobile games, serious games

DOI: 10.3233/JAD-180224

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1285-1293, 2018