Journal of Alzheimer's Disease - Volume 62, issue 4

Authors: Popelová, Andrea | Pražienková, Veronika | Neprašová, Barbora | Kasperová, Barbora Judita | Hrubá, Lucie | Holubová, Martina | Zemenová, Jana | Blum, David | Železná, Blanka | Galas, Marie-Christine | Kuneš, Jaroslav | Maletínská, Lenka

Article Type: Research Article

Abstract: Obesity and type 2 diabetes mellitus (T2DM) were characterized as risk factors for Alzheimer’s disease (AD) development. Subsequently, T2DM drugs, such as liraglutide, were proven to be neuroprotective compounds attenuating levels of amyloid deposits, and tau hyperphosphorylation, both hallmarks of AD. The central anorexigenic effects of liraglutide inspired us to examine the potential neuroprotective effects of palm11 -PrRP31, a strong anorexigenic analog with glucose-lowering properties, in THY-Tau22 mice overexpressing mutated human tau, a model of AD-like tau pathology. Seven-month-old THY-Tau22 mice were subcutaneously infused with palm11 -PrRP31 for 2 months. Spatial memory was tested before and after the treatment, using …a Y-maze. At the end of the treatment, mice were sacrificed by decapitation and hippocampi were dissected and analyzed by immunoblotting with specific antibodies. Treatment with palm11 -PrRP31 resulted in significantly improved spatial memory. In the hippocampi of palm11 -PrRP31-treated THY-Tau22 mice, tau protein phosphorylation was attenuated at Thr231, Ser396, and Ser404, the epitopes linked to AD progression. The mechanism of this attenuation remains unclear, since the activation of those kinases most implicated in tau hyperphosphorylation, such as GSK-3β, JNK, or MAPK/ERK1/2, remained unchanged by palm11 -PrRP31 treatment. Furthermore, we observed a significant increase in the amount of postsynaptic density protein PSD95, and a non-significant increase of synaptophysin, both markers of increased synaptic plasticity, which could also result in improved spatial memory of THY-Tau22 mice treated with palm11 -PrRP31. Palm11 -PrRP31 seems to be a potential tool for the attenuation of neurodegenerative disorders in the brain. However, the exact mechanism of its action must be elucidated. Show more

Keywords: Alzheimer’s disease, palm11-PrRP31, spatial memory, synaptic plasticity, tau hyperphosphorylation, THY-Tau22 mice

DOI: 10.3233/JAD-171041

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1725-1736, 2018

Authors: Gu, Jianlan | Jin, Nana | Ma, Denglei | Chu, Dandan | Iqbal, Khalid | Gong, Cheng-Xin | Liu, Fei

Article Type: Research Article

Abstract: Impairment of cerebral glucose uptake/metabolism in individuals with Alzheimer’s disease (AD) is believed to lead to downregulation of protein O-GlcNAcylation, which contributes to tau pathogenesis through tau hyperphosphorylation. Level of glucose transporter 3 (GLUT3), a neuronal specific glucose transporter, is decreased in AD brain, which may contribute to impaired brain glucose uptake/metabolism. However, what causes the reduction of GLUT3 in AD brain is not fully understood. Here, we report 1) that decrease of GLUT3 is associated with the reduction of protein O-GlcNAcylation in AD brain, 2) that GLUT3 level is negatively correlated with calpain I activation in human brain, 3) …that calpain I proteolyzes GLUT3 at the N-terminus in vitro , and 4) that activation of calpain I is negatively correlated with protein O-GlcNAcylation in AD brain. Furthermore, we found that overexpression of GLUT3 enhances protein O-GlcNAcylation in N2a cells. Overexpression of calpain I suppresses protein O-GlcNAcylation in these cells. These findings suggest a novel mechanism by which calpain I overactivation leads to GLUT3 degradation and the consequent down-regulation of protein O-GlcNAcylation in AD brain. Show more

Keywords: Alzheimer’s disease, calpain I, glucose transporter 3, protein O-GlcNAcylation

DOI: 10.3233/JAD-171047

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1737-1746, 2018

Authors: Cations, Monica | Draper, Brian | Low, Lee-Fay | Radford, Kylie | Trollor, Julian | Brodaty, Henry | Sachdev, Perminder | Gonski, Peter | Broe, Gerald Anthony | Withall, Adrienne

Article Type: Research Article

Abstract: Background: Several brain reserve, vascular risk, and other modifiable factors have been associated with late-onset dementia, but their association with young onset dementia (YOD) has not been adequately explored. Objective: To examine the association of cognitive reserve enhancing factors, cardiovascular risk factors (including smoking), depression, alcohol use, and traumatic brain injury (TBI) with non-autosomal dominant degenerative and/or vascular YOD. Methods: Data for this matched case-control study were taken from two larger studies conducted in NSW, Australia. One comprised all people with YOD within a geographical region, while the other exclusively included Aboriginal and Torres Strait Islander …participants. Dementia diagnosis was confirmed by clinical consensus, and risk exposure was retrospectively self- and/or informant-reported. Results: Participants were 96 people with YOD (58.4% with probable Alzheimer’s disease) and 175 age-group, sex, and sample matched control participants. Poor educational attainment, low participation in cognitive leisure activity, stroke, transient ischemic attack, and self-reported very heavy alcohol use were related to the risk of primary degenerative and/or vascular YOD. The effect of hypertension and depression varied depending on when they occurred relative to dementia onset. Current smoking was significantly associated with risk in univariate analyses but did not retain significance in multivariate modelling. There was no association with hypercholesterolemia, diabetes, or TBI of any kind. Some compensation for low educational attainment was possible via a complex occupation later in life. Conclusion: Non-genetic factors have a role in YOD, though the relative importance of each factor may be different to late onset dementia. The timing and severity of exposure, as well as the potential for compensation with later protective exposures, are important considerations for potential prevention strategies. Show more

Keywords: Alzheimer’s disease, early onset dementia, epidemiology, frontotemporal, Lewy body, lifestyle, modifiable, protective, risk, vascular, young onset dementia

DOI: 10.3233/JAD-171027

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1747-1758, 2018

Authors: Kreisl, William Charles | Jin, Peng | Lee, Seonjoo | Dayan, Ezra R. | Vallabhajosula, Shankar | Pelton, Gregory | Luchsinger, José A. | Pradhaban, Gnanavalli | Devanand, D.P.

Article Type: Research Article

Abstract: Background: Odor identification deficits occur in Alzheimer’s disease (AD), as measured by the 40-item University of Pennsylvania Smell Identification Test (UPSIT). Objective: To determine if UPSIT scores predict amyloid-β (Aβ) status, determined by 11 C-Pittsburgh Compound B PET. We also compared UPSIT scores to Aβ status in predicting future memory decline. Methods: Subjects were recruited into a longitudinal clinical prediction study. We analyzed data from those who had UPSIT, cognitive testing, PIB PET, and at least 12 months’ clinical follow-up. Forty-six amnestic mild cognitive impairment patients and 25 cognitively normal controls were included. Amyloid-positivity was defined …as composite PIB standardized uptake value ratio >1.5. Logistic regression and Receiver Operating Characteristic Curve analyses tested the predictive utility of impaired olfaction (defined as UPSIT score <35) and amyloid-positivity for memory decline. Results: High UPSIT scores predicted absence of amyloidosis on PET, with negative predictive value of 100%. Positive predictive value of low UPSIT scores on positive Aβ status was only 41%. Both low UPSIT score (OR = 4.301, 95% CI = 1.248, 14.821, p  = 0.021) and positive PET scan (OR = 20.898, 95% CI = 2.222, 196.581, p  = 0.008) predicted memory decline. Conclusion: Individuals with high UPSIT scores are less likely to have cerebral amyloidosis or experience memory decline. Therefore, UPSIT has potential as a screening tool to determine utility of Aβ PET in clinical practice or enrollment in clinical trials. Low UPSIT score is a non-specific marker of neurodegeneration that could indicate further workup in patients with memory complaints. Show more

Keywords: Alzheimer’s disease, amyloid, olfactory perception, positron emission tomography

DOI: 10.3233/JAD-170960

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1759-1766, 2018

Authors: Ito, Naoki | Saito, Hitomi | Seki, Shinobu | Ueda, Fumitaka | Asada, Takashi

Article Type: Research Article

Abstract: Background: Dementia and its first or transitional stage, mild cognitive impairment (MCI), is a major concern for the aging Japanese society. Thus, the use of dietary supplements to improve or maintain cognitive function has become a topic of public interest. Objective: In this study, we evaluated the effects of a composite supplement containing food-derived antioxidants, specifically astaxanthin and sesamin (AS), on cognitive function in people with MCI. Method: Twenty-one healthy participants with MCI were recruited in our double-blind placebo-controlled pilot study. They were assigned to either an AS group, who received ingestible capsules containing AS, or …a placebo group, who received identical placebo capsules. To assess cognitive functions, we performed the Japanese version of the Central Nervous System Vital Signs (CNSVS) test and the Alzheimer’s Disease Assessment Scale-Cog test at baseline, after 6 weeks, and after 12 weeks of dietary supplementation. Results: The CNSVS test revealed significant improvements in psychomotor speed and processing speed in the AS group compared with the placebo group, suggesting that the daily supplementation of AS improved cognitive functions related to the ability to comprehend, and perform complex tasks quickly and accurately. Conclusion: Our results provide support for the use of AS as a dietary supplementation for improving cognitive functions. Show more

Keywords: Astaxanthin, CNSVS, cognitive functions, mild cognitive impairment, sesame extract, sesamin

DOI: 10.3233/JAD-170969

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1767-1775, 2018

Authors: Kim, Woojin Scott | Fu, Yuhong | Dobson-Stone, Carol | Hsiao, Jen-Hsiang T. | Shang, Kani | Hallupp, Marianne | Schofield, Peter R. | Garner, Brett | Karl, Tim | Kwok, John B.J.

Article Type: Research Article

Abstract: Alzheimer’s disease is characterized by abnormal amyloid-β (Aβ) peptide accumulation beginning decades before symptom onset. An effective prophylactic treatment aimed at arresting the amyloidogenic pathway would therefore need to be initiated prior to the occurrence of Aβ pathology. The SIGMAR1 gene encodes a molecular chaperone that modulates processing of the amyloid-β protein precursor (AβPP). Fluvoxamine is a selective serotonin reuptake inhibitor and a potent SIGMAR1 agonist. We therefore hypothesized that fluvoxamine treatment would reduce Aβ production and improve cognition. We firstly investigated the impact of SIGMAR1 on AβPP processing, and found that overexpression and knockdown of SIGMAR1 significantly …affected γ -secretase activity in SK-N-MC neuronal cells. We then tested the impact of fluvoxamine on Aβ production in an amyloidogenic cell model, and found that fluvoxamine significantly reduced Aβ production by inhibiting γ -secretase activity. Finally, we assessed the efficacy of long-term treatment (i.e., ∼8 months) of 10 mg/kg/day fluvoxamine in the J20 amyloidogenic mouse model; the treatment was initiated prior to the occurrence of predicted Aβ pathology. Physical examination of the animals revealed no overt pathology or change in weight. We conducted a series of behavioral tests to assess learning and memory, and found that the fluvoxamine treatment significantly improved memory function as measured by novel object recognition task. Two other tests revealed no significant change in memory function. In conclusion, fluvoxamine has a clear impact on γ -secretase activity and AβPP processing to generate Aβ, and may have a protective effect on cognition in the J20 mice. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, cognition, fluvoxamine, J20, SIGMAR1

DOI: 10.3233/JAD-171001

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1777-1787, 2018

Authors: Zhang, Yanmin | Guo, Ouyang | Huo, Yuda | Wang, Guan | Man, Heng-Ye

Article Type: Research Article

Abstract: As the primary mediator for synaptic transmission, AMPA receptors (AMPARs) are crucial for synaptic plasticity and higher brain functions. A downregulation of AMPAR expression has been indicated as one of the early pathological molecular alterations in Alzheimer’s disease (AD), presumably via amyloid-β (Aβ). However, the molecular mechanisms leading to the loss of AMPARs remain less clear. We report that in primary neurons, application of Aβ triggers AMPAR internalization accompanied with a decrease in cell-surface AMPAR expression. Importantly, in both Aβ-treated neurons and human brain tissue from AD patients, we observed a significant decrease in total AMPAR amount and an …enhancement in AMPAR ubiquitination. Consistent with facilitated receptor degradation, AMPARs show higher turnover rates in the presence of Aβ. Furthermore, AD brain lysates and Aβ-incubated neurons show increased expression of the AMPAR E3 ligase Nedd4 and decreased expression of AMPAR deubiquitinase USP46. Changes in these enzymes are responsible for the Aβ-dependent AMPAR reduction. These findings indicate that AMPAR ubiquitination acts as the key molecular event leading to the loss of AMPARs and thus suppressed synaptic transmission in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, AMPA receptor, degradation, Nedd4, ubiquitination, USP46

DOI: 10.3233/JAD-170879

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1789-1801, 2018

Authors: Hou, Ting-Ting | Yang, He-Yun | Wang, Wei | Wu, Qiao-Qi | Tian, Yuan-Ruhua | Jia, Jian-Ping

Article Type: Research Article

Abstract: Abnormal amyloid-β (Aβ) aggregates are a striking feature of Alzheimer’s disease (AD), and Aβ oligomers have been proven to be crucial in the pathology of AD. Any intervention targeting the generation or aggregation of Aβ can be expected to be useful in AD treatment. Oxidative stress and inflammation are common pathological changes in AD that are involved in the generation and aggregation of Aβ. In the present study, 6-month-old PS1V97L transgenic (Tg) mice were treated with sulforaphane, an antioxidant, for 4 months, and this treatment significantly inhibited the generation and aggregation of Aβ. Sulforaphane also alleviated several downstream pathological changes …that including tau hyperphosphorylation, oxidative stress, and neuroinflammation. Most importantly, the cognition of the sulforaphane-treated PS1V97L Tg mice remained normal compared to that of wild-type mice at 10 months of age, when dementia typically emerges in PS1V97L Tg mice. Pretreating cultured cortical neurons with sulforaphane also protected against neuronal injury caused by Aβ oligomers in vitro . These findings suggest that sulforaphane may be a potential compound that can inhibit Aβ oligomer production in AD. Show more

Keywords: Aβ oligomer, Alzheimer’s disease, inflammation, oxidative stress, sulforaphane

DOI: 10.3233/JAD-171110

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1803-1813, 2018

Authors: Kamara, Dennis M. | Gangishetti, Umesh | Gearing, Marla | Willis-Parker, Monica | Zhao, Liping | Hu, William T. | Walker, Lary C.

Article Type: Research Article

Abstract: Cerebral amyloid angiopathy (CAA) of the Aβ type is variably present in the brains of patients with Alzheimer’s disease (AD). CAA contributes to cognitive decline and increases the risk of lobar hemorrhage; because both AD-typical dementia and lobar hemorrhage are more common in African-Americans than in Caucasians, we postulated that African-Americans with AD might be particularly susceptible to CAA. To test this hypothesis, we analyzed CAA histopathologically in the large vessels and capillaries of autopsy-derived frontal, temporal, parietal, and occipital cortical samples from African-Americans (n  = 18) and Caucasians (n  = 19) with end-stage AD. In the combined cohort of 37 subjects, …22% of the subjects had severe CAA in large vessels, and 11% had severe CAA in capillaries. However, the prevalence and histopathologic characteristics of CAA were similar in the African-Americans and Caucasians. This conclusion was substantiated in an independent sample from the National Alzheimer’s Coordinating Center database, in which the degree of CAA was comparable in 1,554 Caucasians and 68 African-Americans with end-stage AD. These findings support a growing consensus that the fundamental histopathologic features of AD are largely impartial to the race of the afflicted. Show more

Keywords: Aβ, aging, amyloid, cerebrovascular amyloidosis, dementia, ethnicity, race, tauopathy, vascular disease

DOI: 10.3233/JAD-170954

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1815-1826, 2018

Authors: Bouts, Mark J.R.J. | Möller, Christiane | Hafkemeijer, Anne | van Swieten, John C. | Dopper, Elise | van der Flier, Wiesje M. | Vrenken, Hugo | Wink, Alle Meije | Pijnenburg, Yolande A.L. | Scheltens, Philip | Barkhof, Frederik | Schouten, Tijn. M. | de Vos, Frank | Feis, Rogier A. | van der Grond, Jeroen | de Rooij, Mark | Rombouts, Serge A.R.B.

Article Type: Research Article

Abstract: Background/Objective: Overlapping clinical symptoms often complicate differential diagnosis between patients with Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Magnetic resonance imaging (MRI) reveals disease specific structural and functional differences that aid in differentiating AD from bvFTD patients. However, the benefit of combining structural and functional connectivity measures to—on a subject-basis—differentiate these dementia-types is not yet known. Methods: Anatomical, diffusion tensor (DTI), and resting-state functional MRI (rs-fMRI) of 30 patients with early stage AD, 23 with bvFTD, and 35 control subjects were collected and used to calculate measures of structural and functional tissue status. All measures were …used separately or selectively combined as predictors for training an elastic net regression classifier. Each classifier’s ability to accurately distinguish dementia-types was quantified by calculating the area under the receiver operating characteristic curves (AUC). Results: Highest AUC values for AD and bvFTD discrimination were obtained when mean diffusivity, full correlations between rs-fMRI-derived independent components, and fractional anisotropy (FA) were combined (0.811). Similarly, combining gray matter density (GMD), FA, and rs-fMRI correlations resulted in highest AUC of 0.922 for control and bvFTD classifications. This, however, was not observed for control and AD differentiations. Classifications with GMD (0.940) and a GMD and DTI combination (0.941) resulted in similar AUC values (p  = 0.41). Conclusion: Combining functional and structural connectivity measures improve dementia-type differentiations and may contribute to more accurate and substantiated differential diagnosis of AD and bvFTD patients. Imaging protocols for differential diagnosis may benefit from also including DTI and rs-fMRI. Show more

Keywords: Alzheimer’s disease, behavioral variant frontotemporal dementia, classification, differential diagnosis, diffusion tensor imaging, functional MRI, machine learning

DOI: 10.3233/JAD-170893

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1827-1839, 2018