Journal of Alzheimer's Disease - Volume 45, issue 3

Authors: Yang, Hongkuan | Guan, Hongpeng | Yang, Mingchun | Liu, Ziyi | Takeuchi, Shigeko | Yanagisawa, Daijiro | Vincent, Steven R. | Zhao, Shiguang | Tooyama, Ikuo

Article Type: Research Article

Abstract: Studies have shown an increased expression of mitochondrial ferritin (FtMt) and an antioxidant role for the protein in the brains of Alzheimer's disease (AD) patients. However, little information is available concerning the role of FtMt in other AD pathologies, including inflammation and amyloidogenesis. Therefore, we investigated the regulation and function of FtMt in inflammation and amyloidogenesis. FtMt protein expression was increased by proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin 6 (IL-6), whereas FtMt mRNA levels were increased by TNF-α but not by IL-1β or IL-6 in IMR-32 cells. The transcription factor nuclear factor-κB (NF-κB) inhibitor, Bay …11-7082, suppressed this TNF-α–induced FtMt expression. FtMt overexpression increased NF-κB activity and translocation of p65 into the nucleus in HEK293 cells. Conversely, knockdown of FtMt attenuated TNF-α–induced NF-κB activity. Overexpression of FtMt inhibited TNF-α-induced apoptosis in the cell culture. FtMt overexpression reduced iron-mediated expression of amyloid-β protein precursor and decreased NF-κB-dependent increases in β- and γ-secretase, leading to decreased amyloid-β production. Our data provide new insights into the mechanism underlying the regulation of FtMt expression by proinflammatory cytokines and indicate further roles for FtMt in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, inflammation, iron, mitochondrial ferritin, NF-κB

DOI: 10.3233/JAD-142595

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 797-811, 2015

Authors: Struyfs, Hanne | Van Broeck, Bianca | Timmers, Maarten | Fransen, Erik | Sleegers, Kristel | Van Broeckhoven, Christine | De Deyn, Peter P. | Streffer, Johannes R. | Mercken, Marc | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Overlapping cerebrospinal fluid biomarkers (CSF) levels between Alzheimer’s disease (AD) and non-AD patients decrease differential diagnostic accuracy of the AD core CSF biomarkers. Amyloid-β (Aβ) isoforms might improve the AD versus non-AD differential diagnosis. Objective: To determine the added diagnostic value of Aβ isoforms, Aβ1-37 , Aβ1-38 , and Aβ1-40 , as compared to the AD CSF biomarkers Aβ1-42 , T-tau, and P-tau181P . Methods: CSF from patients with dementia due to AD (n = 50), non-AD dementias (n = 50), mild cognitive impairment due to AD (n = 50) and non-demented controls (n = …50) was analyzed with a prototype multiplex assay using MSD detection technology. The non-AD group consisted of frontotemporal dementia (FTD; n = 17), dementia with Lewy bodies (DLB; n = 17), and vascular dementia (n = 16). Results: Aβ1-37 and Aβ1-38 increased accuracy to differentiate AD from FTD or DLB. Aβ1-37 , Aβ1-38 , and Aβ1-40 levels correlated with Mini-Mental State Examination scores and disease duration in dementia due to AD. The Aβ1-42 /Aβ1-40 ratio improved diagnostic performance of Aβ1-42 in most differential diagnostic situations. Aβ1-42 levels were lower in APOE ε4 carriers compared to non-carriers. Conclusions: Aβ isoforms help to differentiate AD from FTD and DLB. Aβ isoforms increase diagnostic performance of Aβ1-42 . In contrast to Aβ1-42 , Aβ isoforms seem to be correlated with disease severity in AD. Adding the Aβ isoforms to the current biomarker panel could enhance diagnostic accuracy. Show more

Keywords: Alzheimer's disease, amyloid, biological markers, cerebrospinal fluid, diagnosis, differential, mild cognitive impairment

DOI: 10.3233/JAD-141986

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 813-822, 2015

Authors: Špolcová, Andrea | Mikulášková, Barbora | Holubová, Martina | Nagelová, Veronika | Pirnik, Zdenko | Zemenová, Jana | Haluzík, Martin | Železná, Blanka | Galas, Marie-Christine | Maletínská, Lenka

Article Type: Research Article

Abstract: Numerous epidemiological and experimental studies have demonstrated that patients who suffer from metabolic disorders, such as type 2 diabetes mellitus (T2DM) or obesity, have higher risks of cognitive dysfunction and of Alzheimer's disease (AD). Impaired insulin signaling in the brain could contribute to the formation of neurofibrillary tangles, which contain an abnormally hyperphosphorylated tau protein. This study aimed to determine whether potential tau hyperphosphorylation could be detected in an obesity-induced pre-diabetes state and whether anorexigenic agents could affect this state. We demonstrated that 6-month-old mice with monosodium glutamate (MSG) obesity, which represent a model of obesity-induced pre-diabetes, had increased tau …phosphorylation at Ser396 and Thr231 in the hippocampus compared with the controls, as determined by western blots. Two weeks of subcutaneous treatment with a lipidized analog of prolactin-releasing peptide (palm-PrRP31) or with the T2DM drug liraglutide, which both had a central anorexigenic effect, resulted in increased phosphorylation of the insulin cascade kinases PDK1 (Ser241), Akt (Thr308), and GSK-3β (Ser9). Furthermore, these drugs attenuated phosphorylation at Ser396, Thr231, and Thr212 of tau and of the primary tau kinases in the hippocampi of 6-month-old MSG-obese mice. We identified tau hyperphosphorylation in the obesity-induced pre-diabetes state in MSG-obese mice and demonstrated the beneficial effects of palm-PrRP31 and liraglutide, both of known central anorexigenic effects, on hippocampal insulin signaling and on tau phosphorylation. Show more

Keywords: Alzheimer's disease, insulin signaling, liraglutide, monosodium glutamate-obese mice, obesity, pre-diabetes, prolactin-releasing peptide, tau phosphorylation

DOI: 10.3233/JAD-143150

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 823-835, 2015

Authors: Lee, Doo Young | Moon, Jangsup | Lee, Soon-Tae | Jung, Keun-Hwa | Park, Dong-Kyu | Yoo, Jung-Seok | Sunwoo, Jun-Sang | Byun, Jung-Ick | Shin, Jung-Won | Jeon, Daejong | Jung, Ki-Young | Kim, Manho | Lee, Sang Kun | Chu, Kon

Article Type: Research Article

Abstract: With the recent advancement in transcriptome-wide profiling approach, numerous non-coding transcripts previously unknown have been identified. Among the non-coding transcripts, long non-coding RNAs (lncRNAs) have received increasing attention for their capacity to modulate transcriptional regulation. Although alterations in the expressions of non-coding RNAs have been studied in Alzheimer's disease (AD), most research focused on the involvement of microRNAs, and comprehensive expression profiling of lncRNAs in AD has been lacking. In this study, microarray analysis was performed to procure the expression profile of lncRNAs dysregulated in a triple transgenic model of AD (3xTg-AD). A total of 4,622 lncRNAs were analyzed: 205 …lncRNAs were significantly dysregulated in 3xTg-AD compared with control mice, and 230 lncRNAs were significantly dysregulated within 3xTg-AD in an age-dependent manner (≥2.0-fold, p < 0.05). Among these, 27 and 15 lncRNAs, respectively, had adjacent protein-coding genes whose expressions were also significantly dysregulated. A majority of these lncRNAs and their adjacent genes shared the same direction of dysregulation. For these pairs of lncRNAs and adjacent genes, significant Gene Ontology terms were DNA-dependent regulation of transcription, transcription regulator activity, and embryonic organ morphogenesis. One of the most highly upregulated lncRNAs had a 395 bp core sequence that overlapped with multiple chromosomal regions. This is the first study that comprehensively identified dysregulated lncRNAs in 3xTg-AD mice and will likely facilitate the development of therapeutics targeting lncRNAs in AD. Show more

Keywords: Alzheimer's disease, gene ontology, long non-coding RNAs, microarray, 3xTg-AD

DOI: 10.3233/JAD-142919

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 837-849, 2015

Authors: Khondoker, Mizanur | Newhouse, Stephen | Westman, Eric | Muehlboeck, J-Sebastian | Mecocci, Patrizia | Vellas, Bruno | Tsolaki, Magda | Kłoszewska, Iwona | Soininen, Hilkka | Lovestone, Simon | Dobson, Richard | Simmons, Andrew | for the AddNeuroMed consortium and for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a highly heritable disease, but until recently few replicated genetic markers have been identified. Markers identified so far are likely to account for only a tiny fraction of the heritability of AD and many more genetic risk alleles are thought to be undiscovered. Objective: Identifying genetic markers for AD using combined analysis of genetics and brain imaging data. Methods: Imaging quantitative trait loci (iQTLs) has recently emerged as an interesting research area for linking genetics of brain changes to AD. We consider a genome-wide association scan of 109 brain-wide regional imaging …phenotypes to identify genetic susceptibility loci for AD from a combined set of 1,045 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the AddNeuroMed studies. We use one-SNP-at-a-time as well as multi-SNP Hyperlasso based iQTL methods for the analysis. Results: We identified several novel markers associated with AD, namely HOMER2 (rs1256429; intronic, p = 8.7 × 10−10 ), EOMES (rs2724509; flanking), JAM2 (rs2829841; intronic), and WEE1 (rs10770042; coding). The SNP rs1256429 (HOMER2) was one of the top hits in Hyperlasso as well as in the single-SNP analysis showing an association with the volume of the right thalamus and AD, a brain region reported to be linked with AD in several studies. Conclusion: We believe that the markers identified in this study are novel additions to the existing list of genetic variants associated with AD which can be validated in future replicated studies. Show more

Keywords: Alzheimer's disease, genome wide association study, imaging quantitative trait loci, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-142214

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 851-864, 2015

Authors: Inzelberg, Rivka | Massarwa, Magda | Schechtman, Edna | Strugatsky, Rosa | Farrer, Lindsay A. | Friedland, Robert P.

Article Type: Research Article

Abstract: Background: Vascular risk factors and lack of formal education may increase the risk of Alzheimer’s disease (AD). Objective: To determine the contribution of vascular risk factors and education to the risk of mild cognitive impairment (MCI) and AD and to estimate the risk for conversion from MCI to AD. Methods: This door-to-door survey was performed by an Arab-speaking team in Wadi Ara villages in Israel. All consenting residents aged ≥ 65 years were interviewed for medical history and underwent neurological and cognitive examinations. Individuals were cognitively classified as normal (CN), MCI, AD, vascular dementia, or unclassifiable. …MCI patients were re-examined at least one year later to determine conversion to AD. The contributions of age, gender, school years, and vascular risk factors to the probability of conversion were estimated using logistic regression models. Results: Of the 906 participants, 297 (33%) had MCI and 95 (10%) had AD. Older age (p = 0.0008), female gender (p = 0.023), low schooling (p < 0.0001), and hypertension (p = 0.0002) significantly accounted for risk of MCI versus CN, and diabetes was borderline (p = 0.051). The risk of AD versus CN was significantly associated with age (p < 0.0001), female gender (p < 0.0001), low schooling (p = 0.004) and hypertension (p = 0.049). Of the 231 subjects with MCI that were re-examined, 65 converted to AD. Conclusions: In this population, age, female gender, lack of formal education, and hypertension are risk factors for both AD and MCI. Conversion risk from MCI to AD could be estimated as a function of age, time interval between examinations, and hypertension. Show more

Keywords: Aging, Alzheimer's disease, Arab, mild cognitive impairment, neuroepidemiology, prevalence, risk factors

DOI: 10.3233/JAD-142871

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 865-871, 2015

Authors: Rolstad, Sindre | Berg, Anne Ingeborg | Eckerström, Carl | Johansson, Boo | Wallin, Anders

Article Type: Research Article

Abstract: The neurofilament light (NF-L) subunit is mainly expressed in large-caliber myelinated axons, and elevated concentrations in the cerebrospinal fluid (CSF) are correlated with damage to white matter and subcortical regions. Because the correlation between NF-L and cognition and functional impairment is largely unknown, we investigated associations in patients (n = 622) with (n = 199) and without (n = 423) vascular burden in subjective cognitive impairment (SCI, n = 168), mild cognitive impairment (MCI, n = 261), and dementia (n = 193). Patients were staged according to disease severity and the presence/absence of cerebrovascular disease. CSF amyloid-β1–42 (Aβ1–42 ) …was included in all models due to its concomitant influence on vascular and primary etiology. Linear regression was used to assess associations between NF-L and Aβ1–42 and five cognitive domains of a comprehensive neuropsychological battery as well as with functional impairment using the Clinical Dementia Rating. Changes in these outcomes at the 2-year follow-up were also evaluated. In SCI and MCI patients with vascular burden, higher NF-L concentrations were associated with baseline cognitive performance (β = −0.38 to –0.58) and executive decline (β = −0.44). Lower Aβ1–42 levels were associated with worse cognitive performance in dementia (β = 0.46 to 0.51). In MCI and dementia patients without vascular burden, higher NF-L (β = −0.30 to −0.34) and lower Aβ1–42 concentrations (β = 0.30) were associated with reduced cognitive performance. Higher NF-L concentrations (β = −0.26) were associated with functional decline in patients with vascular burden. CSF NF-L is associated with cognition in patients with and without vascular etiology. These associations were greater in pre-dementia phases in those with vascular etiology and vice versa in those without vascular burden. Show more

Keywords: Amyloid-β1–42, cerebrospinal fluid, cognition, dementia, mild cognitive impairment, neurofilament light subunit, subjective cognitive impairment

DOI: 10.3233/JAD-142694

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 873-881, 2015

Authors: Buratti, Laura | Balestrini, Simona | Altamura, Claudia | Viticchi, Giovanna | Falsetti, Lorenzo | Luzzi, Simona | Provinciali, Leandro | Vernieri, Fabrizio | Silvestrini, Mauro

Article Type: Research Article

Abstract: Background: Defining reliable markers of conversion to dementia could be the first step in order to identify appropriate treatment strategies for mild cognitive impairment (MCI) patients. Objective: To develop a tool able to predict the risk of progression from MCI to Alzheimer’s disease (AD). Methods: 406 MCI patients were included and followed for a one-year period. Demographic characteristics, vascular risk factors, extent of cerebrovascular lesions, markers of carotid atherosclerosis investigated with an ultrasonographic assessment (plaque index and intima-media thickness) and cerebrovascular reactivity to apnea (breath-holding index) were considered as potential predictors of conversion. Results: …106 (26%) MCI patients showed a conversion to AD. Plaque index, intima-media thickness, and breath-holding index were relevant predictors of conversion (p = 0.042; p = 0.003; p < 0.001, multivariate logistic regression analysis). A simplified scoring system was devised based on the magnitude of the estimated multinomial logistic regression β coefficient results. A total score was calculated as the sum of each predictive factor which resulted in a 0–5 range. The optimal cut-off score was ≥3 (sensitivity, 23.6%, 95% CI 15.9%–32.8%; specificity, 97.7%, 95% CI 95.3%–99.1%; positive likelihood ratio, 10.1, 95% CI 4.5%–22.7%; negative likelihood ratio, 0.78, 95% CI 0.70%–0.87%). The AUC was 0.71 (95% CI, 0.65–0.77). Conclusions: Our findings show the possibility to obtain a predictive indicator of the risk of conversion from MCI to dementia by considering the presence of both atherosclerotic changes in the carotid district and impairment of cerebral hemodynamics. Such an approach may allow us to formulate a correct prognosis in more than 70% of patients with amnesic MCI. Show more

Keywords: Alzheimer's disease, atherosclerosis, carotid arteries, cerebral hemodynamics, mild cognitive impairment, ultrasonography

DOI: 10.3233/JAD-143135

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 883-890, 2015

Authors: Hull, Jonathon | Patel, Vinood | El Hindy, Maya | Lee, Christopher | Odeleye, Esther | Hezwani, Mohammed | Love, Seth | Kehoe, Patrick | Chalmers, Katy | Conway, Myra

Article Type: Research Article

Abstract: Background: The human branched chain aminotransferases (hBCATm, mitochondrial and hBCATc, cytosolic) are major contributors to brain glutamate production. This excitatory neurotransmitter is thought to contribute to neurotoxicity in neurodegenerative conditions such as Alzheimer’s disease (AD) but the expression of hBCAT in this disease has not previously been investigated. Objective: The objective of investigating hBCAT expression is to gain insight into potential metabolic pathways that may be dysregulated in AD brain, which would contribute to glutamate toxicity. Methods: Western blot analysis and immunohistochemistry were used to determine the expression and localization of hBCAT in postmortem frontal and …temporal cortex from AD and matched control brains. Results: Western blot analysis demonstrated a significant regional increase in hBCATc expression in the hippocampus (↑ 36%; p-values of 0.012), with an increase of ↑ 160% reported for hBCATm in the frontal and temporal cortex (p-values = 4.22 × 10−4 and 2.79 × 10−5 , respectively) in AD relative to matched controls, with evidence of post-translational modifications to hBCATm, more prominent in AD samples. Using immunohistochemistry, a significant increase in immunopositive labelling of hBCATc was observed in the CA1 and CA4 region of the hippocampus (p-values = 0.011 and 0.026, respectively) correlating with western blot analysis. Moreover, the level of hBCATm in the frontal and temporal cortex correlated significantly with disease severity, as indicated by Braak staging (p-values = 5.63 × 10−6 and 9.29 × 10−5 , respectively). Conclusion: The expression of the hBCAT proteins is significantly elevated in AD brain. This may modulate glutamate production and toxicity, and thereby play a role in the pathogenesis of the disease. Show more

Keywords: Alzheimer's disease, glutamate metabolism, hBCAT

DOI: 10.3233/JAD-142970

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 891-905, 2015

Authors: Chung, Jun Ku | Plitman, Eric | Nakajima, Shinichiro | Chow, Tiffany W. | Chakravarty, M. Mallar | Caravaggio, Fernando | Gerretsen, Philip | Brown, Eric E. | Iwata, Yusuke | Mulsant, Benoit H. | Graff-Guerrero, Ariel | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Mounting evidence associates a lifetime history of major depression (LMD) with an increased risk for Alzheimer's disease (AD). Studies have shown that major depression (MD) is strongly linked to pathophysiological markers of AD, such as cortical amyloid-β (Aβ) burden. However, no imaging studies have shown in vivo whether an LMD is linked to increased Aβ accumulation in patients with mild cognitive impairment (MCI) in four cortical regions that have been highly associated with increased Aβ deposition in previous literature: frontal, cingulate, parietal, and temporal. Drawing from the ADNI database, we found that patients with amnestic MCI (aMCI) and an LMD …(n = 39) had significantly higher 18 F-Florbetapir standardized uptake value ratios, a surrogate measure of Aβ deposition, mainly in the bilateral frontal cortex, compared to patients with aMCI without an LMD (n = 39) (p = 0.02). This difference was not explained by current depressive symptoms, vascular risk factors, or the use of different PET scanners. The results were reliable employing two independent methods for analysis: region-of-interest and voxel-based analyses. Increased Aβ in the bilateral frontal lobes may be a biomarker of depressive symptomology in aMCI patients. Further studies should test whether higher Aβ predicts future conversion into AD in this population. Show more

Keywords: Alzheimer's disease, amyloid-β, major depression, mild cognitive impairment, positron emission tomography

DOI: 10.3233/JAD-142931

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 907-919, 2015