Journal of Alzheimer's Disease - Volume 72, issue 1

Authors: Jääskeläinen, Olli | Solje, Eino | Hall, Anette | Katisko, Kasper | Korhonen, Ville | Tiainen, Mika | Kangas, Antti J. | Helisalmi, Seppo | Pikkarainen, Maria | Koivisto, Anne | Hartikainen, Päivi | Hiltunen, Mikko | Ala-Korpela, Mika | Soininen, Hilkka | Soininen, Pasi | Haapasalo, Annakaisa | Remes, Anne M. | Herukka, Sanna-Kaisa

Article Type: Research Article

Abstract:  Decreased levels of serum high-density lipoprotein (HDL) cholesterol have previously been linked to systemic inflammation and neurodegenerative diseases, such as Alzheimer’s disease. Here, we aimed to analyze the lipoprotein profile and inflammatory indicators, the high-sensitivity C-reactive peptide (hs-CRP) and glycoprotein acetyls (GlycA), in sporadic and C9orf72 repeat expansion-associated frontotemporal lobar degeneration (FTLD) patients. The C9orf72 hexanucleotide repeat expansion is the most frequent genetic etiology underlying FTLD. The concentrations of different lipid measures in the sera of 67 FTLD patients (15 C9orf72 repeat expansion carriers), including GlycA, were analyzed by nuclear magnetic resonance spectroscopy. To verify the state …of systemic inflammation, hs-CRP was also quantified from patient sera. We found that the total serum HDL concentration was decreased in C9orf72 repeat expansion carriers when compared to non-carriers. Moreover, decreased concentrations of HDL particles of different sizes and subclass were consistently observed. No differences were detected in the very low- and low-density lipoprotein subclasses between the C9orf72 repeat expansion carriers and non-carriers. Furthermore, hs-CRP and GlycA levels did not differ between the C9orf72 repeat expansion carriers and non-carriers. In conclusion, the HDL-related changes were linked with C9orf72 repeat expansion associated FTLD but were not seen to associate with systemic inflammation. The underlying reason for the HDL changes remains unclear. Show more

Keywords: C9orf72 protein, cholesterol, frontotemporal dementia, frontotemporal lobar degeneration, inflammation, lipoproteins

DOI: 10.3233/JAD-190132

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 127-137, 2019

Authors: Wang, Yiran | Wang, Ying | Bharti, Veni | Zhou, Hong | Hoi, Vanessa | Tan, Hua | Wu, Zijian | Nagakannan, Pandian | Eftekharpour, Eftekhar | Wang, Jun-Feng

Article Type: Research Article

Abstract: Oxidative stress has been hypothesized to play a role in the pathophysiology of Alzheimer’s disease (AD). Previously, we found that total nitrosylated protein levels were increased in the brain of amyloid-β protein precursor (AβPP) and presenilin 1 (PS1) double transgenic mice, an animal model for AD, suggesting that cysteine oxidative protein modification may contribute to this disease. Thioredoxin (Trx) is a major oxidoreductase that can reverse cysteine oxidative modifications such as sulfenylation and nitrosylation, and inhibit oxidative stress. Thioredoxin-interacting protein (Txnip) is an endogenous Trx inhibitor. To understand the involvement of Trx and Txnip in AD development, we investigated Trx …and Txnip in the brain of AβPP/PS1 mice. Using immunoblotting analysis, we found that although Trx protein levels were not changed, Txnip protein levels were significantly increased in hippocampus and frontal cortex of 9- and 12-month-old AβPP/PS1 mice when compared to wild-type mice. Txnip protein levels were also increased by amyloid-β treatment in primary cultured mouse cerebral cortical neurons and HT22 mouse hippocampal cells. Using biotin switch and dimedone conjugation methods, we found that amyloid-β treatment increased protein nitrosylation and sulfenylation in HT22 cells. We also found that downregulation of Txnip, using CRISPR/Cas9 method in HT22 cells, attenuated amyloid-β-induced protein nitrosylation and sulfenylation. Our findings suggest that amyloid-β may increase Txnip levels, subsequently inhibiting Trx reducing capability and enhancing protein cysteine oxidative modification. Our findings also indicate that Txnip may be a potential target for the treatment of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , nitrosylation, oxidative stress, sulfenylation, thioredoxin, thioredoxin-interacting protein

DOI: 10.3233/JAD-190223

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 139-150, 2019

Authors: Pozueta, Ana | Lage, Carmen | Martínez, María García | Kazimierczak, Martha | Bravo, María | López-García, Sara | Riancho, Javier | González-Suarez, Andrea | Vázquez-Higuera, José Luis | de Arcocha-Torres, María | Banzo, Ignacio | Bonilla, Julio Jimenez | Berciano, José | Rodríguez-Rodríguez, Eloy | Sánchez-Juan, Pascual

Article Type: Research Article

Abstract: Background: Semantic dementia (SD) is a subtype of frontotemporal lobe degeneration characterized by semantic loss, with other cognitive functions initially preserved. SD requires differential diagnosis with Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Semantic knowledge can be evaluated through different tests; however, most of them depend on language. Objective: We describe the development of a brief drawing task that may be helpful for the differential diagnosis of SD. Methods: Seventy-two patients, including 32 AD, 19 bvFTD, and 21 SD were asked to draw 12 items with different age of acquisition and familiarity, belonging to …four different semantic categories. We employed the drawings of healthy volunteers to build a scoring scheme. Results: Turtle, strawberry, train, and envelope were the items of each category that best discriminated between groups and were selected for the Brief drawing task. The discriminatory power of the Brief drawing task between SD versus AD and bvFTD patients, estimated through the area under the curve was 0.84 (95% CI = 0.72–0.96, p  = 0.000007). In a logistic model, the Brief drawing task (p  = 0.003) and VOSP “number location” subtest (p  = 0.016) were significant predictors of the diagnosis of SD versus AD and bvFTD after adjustment by the main covariates. The Brief drawing task provided clinically useful qualitative information. SD drawings were characterized by loss of the distinctive features, intrusions, tendency to prototype, and answers like “I don’t know what this is”. Conclusion: The Brief drawing task appears to reveal deficits in semantic knowledge among patients with SD that may assist in the differential diagnosis with other neurodegenerative diseases. Show more

Keywords: Dementia, differential diagnosis, drawings, semantic dementia, semantic knowledge

DOI: 10.3233/JAD-190660

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 151-160, 2019

Authors: Zyśk, Marlena | Clausen, Fredrik | Aguilar, Ximena | Sehlin, Dag | Syvänen, Stina | Erlandsson, Anna

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the leading cause of dementia worldwide, affecting over 10% of the elderly population. Epidemiological evidence indicates that traumatic brain injury (TBI) is an important risk factor for developing AD later in life. However, which injury-induced processes that contribute to the disease onset remains unclear. The aim with the present study was to identify cellular processes that could link TBI to AD development, by investigating the chronic impact of two different injury models, controlled cortical impact (CCI) and midline fluid percussion injury (mFPI). The trauma was induced in 3-month-old tg-ArcSwe mice, carrying the Arctic mutation along with …the Swedish mutation, and the influence of TBI on AD progression was analyzed at 12- and 24-weeks post-injury. The long-term effect of the TBI on memory deficiency, amyloid-β (Aβ) pathology, neurodegeneration and inflammation was investigated by Morris water maze, PET imaging, immunohistochemistry, and biochemical analyses. Morris water maze analysis demonstrated that mice subjected to CCI or mFPI performed significantly worse than uninjured tg-ArcSwe mice, especially at the later time point. Moreover, the injured mice showed a late upregulation of reactive gliosis, which concurred with a more pronounced Aβ pathology, compared to uninjured AD mice. Our results suggest that the delayed glial activation following TBI may be an important link between the two diseases. However, further studies in both experimental models and human TBI patients will be required to fully elucidate the reasons why TBI increases the risk of neurodegeneration. Show more

Keywords: Alzheimer’s disease, amyloid-β, inflammation, Morris water maze, neurodegeneration astrocytes, PET, traumatic brain injury

DOI: 10.3233/JAD-190572

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 161-180, 2019

Authors: Sutin, Angelina R. | Stephan, Yannick | Terracciano, Antonio

Article Type: Research Article

Abstract: Personality traits, such as higher Neuroticism and lower Conscientiousness, are associated with risk of Alzheimer’s disease and other dementias. A diagnosis of dementia relies, in part, on informant ratings of the individual’s cognitive status. Here we examine whether self-reported personality traits are associated with four measures of informant-rated cognition up to a decade later. Participants from the Health and Retirement Study (N = 2,536) completed a five-factor model measure of personality in 2006 or 2008. Informants completed the 2016 Harmonized Cognitive Assessment Protocol (HCAP), which included ratings of the participant’s current cognitive functioning and change in cognitive function over the last decade …assessed with the IQCODE, Blessed, 1066, and CSID. Controlling for characteristics of the participant, informant, and their relationship, higher Neuroticism and lower Conscientiousness were associated consistently with worse informant-rated cognition. The association between Openness and better informant-rated cognition was due primarily to higher baseline cognitive function. Extraversion and Agreeableness were associated with better informant-rated cognition only among participants who were cognitively intact at follow-up. The present research suggests that knowledgeable informants are able to detect cognitive deficits associated with personality. Show more

Keywords: Cognitive decline, dementia, five factor model, informant-rated cognition

DOI: 10.3233/JAD-190555

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 181-190, 2019

Authors: Chou, Ping-Song | Wu, Meng-Ni | Yang, Chen-Cheng | Shen, Cheng-Ting | Yang, Yuan-Han

Article Type: Research Article

Abstract: Background: Shared links between type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) have been well-known. A high concentration of advanced glycation end products (AGEs) has been reported to contribute to impaired mobility in patients with AD, but there is limited understanding regarding the longitudinal impact of AGEs on cognitive performance. Objective: This study aims to explore whether the concentrations of AGEs mediate the clinical progression of cognitive performance in patients with AD and T2DM. Methods: Twenty-five patients aged 79.0±5.8 years who were diagnosed with probable AD with a Clinical Dementia Rating (CDR) of 0.5 or …1 and T2DM were enrolled in this study. When patients participated in the study, the concentration of plasma AGEs was tested. A series of neuropsychological tests, namely the Mini-Mental Status Examination (MMSE), Cognitive Assessment Screening Instrument (CASI), and CDR, were performed annually during follow-up. The association between the concentration of AGEs and changes in overall cognition and cognition related daily living performance was analyzed. Results: After the mean 48.6±2.1 months of follow-up, AGEs were found to be significantly associated with a change in CDR. A total of 12 (48%) patients experienced a decline in CDR; they had a significantly higher concentration of AGEs than did those whose CDR did not deteriorate (100.5 ± 14.2 versus 81.5 ± 17.7; p  = 0.007). This difference in CDR remained significant after adjustment for age, sex, education level, and apolipoprotein E4 status (adjusted p  = 0.023). Conclusion: In conclusion, this study indicates that a high concentration of AGEs may be a predictor of a long-term decline in cognition related daily living performance in patients with AD and T2DM. Show more

Keywords: Advanced glycation end products, Alzheimer’s disease, clinical dementia rating, diabetes mellitus

DOI: 10.3233/JAD-190639

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 191-197, 2019

Authors: Wang, Qian | Jiang, Hailun | Wang, Linlin | Yi, Hong | Li, Zhuorong | Liu, Rui

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive impairments. Vitegnoside is a flavonoid present in the medicinal plant Vitex negundo , widely used as a folk medicine in several Asian countries including China. It possesses several biological activities, including axon outgrowth, but no evidence is available on its effect on AD. Since no effective treatment is available to cure AD, the effect of vitegnoside on this disease was investigated. The human neuroblastoma SH-SY5Y cell line carrying the Swedish mutation that induces AβPP overexpression was used as an in vitro AD cell model. AβPP overexpression does …not induce toxicity per se unless triggered by copper. Vitegnoside promoted neuroprotection through the improvement of cell viability, maintenance of cytomembrane integrity and nuclear homogeneity in these cells, but these effects were not observed in the copper-treated SH-SY5Y cells without AβPP overexpression used as the wild-type control, indicating that vitegnoside exerted neuroprotection under copper-triggered Aβ toxic conditions. Vitegnoside failed to decrease AβPP expression, Aβ40/42 levels, and oxidative stress due to copper-induced Aβ toxicity. However, its administration protected the mitochondrial function and restored the imbalance between pro-apoptotic and anti-apoptotic proteins. Additionally, vitegnoside inactivated p38 MAPK/MK2, JNK/c-Jun, and downstream NF-κ B inflammatory transductions. Furthermore, the inactivation of p38 MAPK/JNK signaling contributed to vitegnoside-mediated neuroprotection resulting from pharmacological inhibition of p38 MAPK/JNK and in silico interaction prediction. Our study revealed the neuroprotective effect of vitegnoside and its potential mechanisms against copper-induced Aβ neurotoxicity. These findings highlighted the potential therapeutic effect of vitegnoside against AD progression. Show more

Keywords: Alzheimer’s disease, amyloid-β, apoptosis, mitogen-activated protein kinase, vitegnoside

DOI: 10.3233/JAD-190640

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 199-214, 2019

Authors: Toppala, Sini | Ekblad, Laura L. | Lötjönen, Jyrki | Helin, Semi | Hurme, Saija | Johansson, Jarkko | Jula, Antti | Karrasch, Mira | Koikkalainen, Juha | Laine, Hanna | Parkkola, Riitta | Viitanen, Matti | Rinne, Juha O.

Article Type: Research Article

Abstract: Background: Type 2 diabetes (T2DM) increases the risk for Alzheimer’s disease (AD) but not for AD neuropathology. The association between T2DM and AD is assumed to be mediated through vascular mechanisms. However, insulin resistance (IR), the hallmark of T2DM, has been shown to associate with AD neuropathology and cognitive decline. Objective: To evaluate if midlife IR predicts late-life cognitive performance and cerebrovascular lesions (white matter hyperintensities and total vascular burden), and whether cerebrovascular lesions and brain amyloid load are associated with cognitive functioning. Methods: This exposure-to-control follow-up study examined 60 volunteers without dementia (mean age 70.9 …years) with neurocognitive testing, brain 3T-MRI and amyloid-PET imaging. The volunteers were recruited from the Finnish Health 2000 survey (n  = 6062) to attend follow-up examinations in 2014–2016 according to their insulin sensitivity in 2000 and their APOE genotype. The exposure group (n  = 30) had IR in 2000 and the 30 controls had normal insulin sensitivity. There were 15 APOE ɛ 4 carriers per group. Statistical analyses were performed with multivariable linear models. Results: At follow-up the IR+group performed worse on executive functions (p  = 0.02) and processing speed (p  = 0.007) than the IR- group. The groups did not differ in cerebrovascular lesions. No associations were found between cerebrovascular lesions and neurocognitive test scores. Brain amyloid deposition associated with slower processing speed. Conclusion: Midlife IR predicted poorer executive functions and slower processing speed, but not cerebrovascular lesions. Brain amyloid deposition was associated with slower processing speed. The association between midlife IR and late-life cognition might not be mediated through cerebrovascular lesions measured here. Show more

Keywords: Alzheimer’s disease, amyloid, APOE , 11C-PIB, cerebrovascular lesions, cognition, follow-up study, insulin resistance, magnetic resonance imaging, PET scan

DOI: 10.3233/JAD-190691

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 215-228, 2019

Authors: Hamezah, Hamizah Shahirah | Durani, Lina Wati | Yanagisawa, Daijiro | Ibrahim, Nor Faeizah | Aizat, Wan Mohd | Makpol, Suzana | Wan Ngah, Wan Zurinah | Damanhuri, Hanafi Ahmad | Tooyama, Ikuo

Article Type: Research Article

Abstract: Tocotrienol-rich fraction (TRF) is a mixture of vitamin E analogs derived from palm oil. We previously demonstrated that supplementation with TRF improved cognitive function and modulated amyloid pathology in AβPP/PS1 mice brains. The current study was designed to examine proteomic profiles underlying the therapeutic effect of TRF in the brain. Proteomic analyses were performed on samples of hippocampus, medial prefrontal cortex (mPFC), and striatum using liquid chromatography coupled to Q Exactive HF Orbitrap mass spectrometry. From these analyses, we profiled a total of 5,847 proteins of which 155 proteins were differentially expressed between AβPP/PS1 and wild-type mice. TRF supplementation of …these mice altered the expression of 255 proteins in the hippocampus, mPFC, and striatum. TRF also negatively modulated the expression of amyloid beta A4 protein and receptor-type tyrosine-protein phosphatase alpha protein in the hippocampus. The expression of proteins in metabolic pathways, oxidative phosphorylation, and those involved in Alzheimer’s disease were altered in the brains of AβPP/PS1 mice that received TRF supplementation. Show more

Keywords: Alzheimer’s disease, LC-MS, palm oil, proteomics, tocotrienol

DOI: 10.3233/JAD-181171

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 229-246, 2019

Authors: Smeijer, David | Ikram, M. Kamran | Hilal, Saima

Article Type: Research Article

Abstract: Perivascular compartments surrounding the penetrating arteries in the brain are part of a physiologic system, which facilitates fluids exchange and clearance of solutes from the brain. The perivascular compartments become visible on MRI when enlarged and are commonly referred to as perivascular spaces (ePVS). Previous studies on the association between ePVS and dementia have been inconsistent due to varying methods of measuring ePVS. As a frame of reference for future MRI studies on ePVS, we systematically review the literature on ePVS as a marker of vascular brain injury related to dementia from population-based as well as hospital-based settings. We identified …three longitudinal and ten cross-sectional studies involving 7,581 persons. Potential outcomes were all-cause dementia, Alzheimer’s disease, and vascular dementia. There was considerable heterogeneity in ePVS assessment: with studies using either visual inspection or segmentation, examining different brain locations and implementing different grading scales. Moreover, out of the total of 13 studies, all five studies on vascular dementia reported an association with presence of basal ganglia ePVS after adjustment for age, gender, and white matter hyperintensities. For seven studies on Alzheimer’s disease and all-cause dementia, the results were ambiguous. This review did not identify an independent association of ePVS with prevalent or incident dementia. Harmonized methods for ePVS assessment, tested across different populations, may benefit future MRI studies on ePVS and dementia. Show more

Keywords: Cerebral small vessel disease, dementia, enlarged perivascular spaces, magnetic resonance imaging

DOI: 10.3233/JAD-190527

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 247-256, 2019