Journal of Alzheimer's Disease - Volume 72, issue 2

Authors: de la Monte, Suzanne M. | Donahue, John E. | Aswad, Bassam I.

Article Type: Obituary

DOI: 10.3233/JAD-191107

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 361-362, 2019

Authors: Krolak-Salmon, Pierre | Maillet, Audrey | Vanacore, Nicola | Selbaek, Geir | Rejdak, Konrad | Traykov, Latchezar | Politis, Antonios | Georges, Jean | Borson, Soo | Leperre-Desplanques, Armelle

Article Type: Review Article

Abstract: Neurocognitive disorders causing progressive cognitive, functional, and behavioral impairment remain underdiagnosed. The needs for a timely diagnosis are now widely acknowledged since person-centered care helps to preserve life quality and prevent crises. One powerful barrier to detection in primary care is the lack of an easy-to-follow stepwise approach, grounded in evidence and consistent with high-quality specialty practice. To help fill this gap, the current European Joint Action proposes a graduated diagnosis strategy tailored to the patients’ needs and wills, clarifying appropriate components for primary and specialty care. This strategy considers a first evaluation in primary care that may detect a …neurocognitive disorder, that would lead to a second evaluation step allowing etiological diagnosis hypotheses performed mostly by the specialist. A third evaluation stage considering some biological, electrophysiological, or neuroimaging complementary techniques would be proposed to atypical cases or patients willing to consider access to research. Show more

Keywords: Alzheimer’s disease, detection, diagnosis, general practitioner, memory, neurocognitive disorder

DOI: 10.3233/JAD-190461

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 363-372, 2019

Authors: Rossini, Paolo Maria | Cappa, Stefano F. | Lattanzio, Fabrizia | Perani, Daniela | Spadin, Patrizia | Tagliavini, Fabrizio | Vanacore, Nicola

Article Type: Research Article

Abstract: Alzheimer’s disease is the most common age-related neurodegenerative disorder and its burden on patients, families, and society grows significantly with lifespan. Early modifications of risk-enhancing lifestyles and treatment initiation expand personal autonomy and reduce management costs. Many clinical trials with potentially disease-modifying drugs are devoted to mild cognitive impairment (MCI) prodromal-to-Alzheimer’s disease. The identification of biomarkers for early diagnosis may thus be crucial for early intervention and identification of high-risk subjects, the most appropriate target of new drugs as soon as they will be discovered. INTERCEPTOR is a strategic project by the Italian Ministry of Health and the Italian Medicines …Agency (AIFA), aiming to validate the best combination (highly accurate, non-invasive, available on the whole national territory and financially sustainable) of biomarkers and organizational model for early diagnosis. 500 MCI subjects will be enrolled at baseline and followed-up for 3 years for at least 400 of them in order to define a “hub & spoke” nationwide model with recruiting (spokes) centers for MCI identification and expert (hubs) centers for risk diagnosis. Show more

Keywords: Alzheimer’s disease, biomarkers, early diagnosis, healthcare organizational models, mild cognitive impairment, prodromal Alzheimer’s disease, public health

DOI: 10.3233/JAD-190670

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 373-388, 2019

Authors: Jiang, Juanjuan | Yan, Zhuangzhi | Sheng, Can | Wang, Min | Guan, Qinglan | Yu, Zhihua | Han, Ying | Jiang, Jiehui

Article Type: Research Article

Abstract: Background: Detecting subtle changes in visual attention from electroencephalography (EEG) and the perspective of eye movement in mild cognitive impairment (MCI) patients can be of great significance in screening early Alzheimer’s disease (AD) in a large population at primary care. Objective: We proposed an automatic, non-invasive, and quick MCI detection approach based on multimodal physiological signals for clinical decision-marking. Methods: The proposed model recruited 152 patients with MCI and 184 healthy elderly controls (HC) who underwent EEG and eye movement signal recording under a visual stimuli task, as well as other neuropsychological assessments. Forty features were …extracted from EEG and eye movement signals by linear and nonlinear analysis. The features related to MCI were selected by logistic regression analysis. To evaluate the efficacy of this MCI detection approach, we applied the same procedures to achieve the Clinical model, EEG model, Eye movement model, EEG+ Clinical model, Eye movement+ Clinical model, and Combined model, and compared the classification accuracy between the MCI and HC groups with the above six models. Results: After the penalization of logistic regression analysis, five features from EEG and eye movement features exhibited significant differences (p  < 0.05). In the classification experiment, the combined model resulted in the best accuracy. The average accuracy for the Clinical/EEG/Eye movement/EEG+ Clinical/Eye movement+ Clinical/Combined model was 68.69%, 61.79%, 73.13%, 69.46%, 75.61%, and 81.51%, respectively. Conclusion: These results suggest that the proposed MCI detection tool has the potential to screen MCI patients from HCs and may be a powerful tool for personalized precision MCI screening in the large-scale population under primary care condition. Show more

Keywords: Attention, electroencephalography, eye movement, mild cognitive impairment, multimodal detection, 2017LCSY345

DOI: 10.3233/JAD-190628

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 389-399, 2019

Authors: La Rosa, Francesca | Saresella, Marina | Marventano, Ivana | Piancone, Federica | Ripamonti, Enrico | Al-Daghri, Nasser | Bazzini, Chiara | Zoia, Chiara Paola | Conti, Elisa | Ferrarese, Carlo | Clerici, Mario

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is associated with the accumulation of amyloid-β (Aβ) within senile plaques in the brain and neuroinflammation, possibly driven by the activation of the NLRP3 inflammasome. Nucleoside reverse transcriptase inhibitors (NRTI) hamper the NLRP3 inflammasome assembly. Objective: We utilized an in vitro model reproducing the Aβ-driven inflammation seen in AD to analyze whether stavudine (D4T), a prototypical NRTI, modulates Aβ-mediated inflammasome activation and the ability of macrophages to eliminate Aβ via phagocytosis and autophagy. Methods: THP-1-derived macrophages were stimulated in vitro with Aβ42 or with Aβ42 after LPS-priming …in the presence/absence of D4T. NLRP3 and TREM2 expression was analyzed by RT-PCR; phagocytosis, as well as ASC-Speck formation, was analyzed by Amnis FlowSight Imaging; NLRP3-produced cytokines were quantified by ELISA and, finally, autophagy was analyzed by measuring p-ERK1/2, p-AKT, beclin, p70-S6Kinase, and Lamp by ELISA and western blot. Results: IL-1β, IL-18, and caspase-1 were increased whereas Aβ phagocytosis and TREM2 were reduced in LPS+Aβ42 -stimulated cells. D4T reduced NLRP3 assembly as well as IL-18 and caspase-1 production, but did not affect IL-1β production and TREM2 expression. Notably, whereas D4T reduced Aβ phagocytosis, Aβ autophagy by macrophages was stimulated by D4T, as witnessed by the down-modulation of ERK1/2 and AKT phosphorylation and the upregulation of beclin, LAMP, and p70-S6K, their downstream targets. Conclusion: In this in vitro model of AD, D4T reduces NLRP3 inflammasome-associated inflammation and stimulates Aβ autophagy by macrophages. It will be interesting to verify the possibly beneficial effects of D4T in the clinical scenario. Show more

Keywords: Alzheimer’s disease, amyloid-β phagocytosis, autophagy, cytokines, D4T, NLRP3-inflammasome

DOI: 10.3233/JAD-181259

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 401-412, 2019

Authors: Zou, Shengzhen | Zhang, Jie | for Alzheimer’s Disease Neuroimaging Initiative | Chen, Wei

Article Type: Research Article

Abstract: Apolipoproteins (APOs) have been implicated in the pathogenesis of Alzheimer’s disease (AD). In the present study, we aimed to investigate if patterns of cerebrospinal fluid (CSF) APOs (APOA-I, APOC-III, APOD, APOE, APOH, and APOJ) levels are associated with changes over time in cognition, memory performance, neuroimaging markers, and AD-related pathologies (CSF Aβ42 , t-tau, and p-tau) in non-demented older adults. At baseline, a total of 241 non-demented older adults with CSF APOs data was included in the present analysis. Hierarchical agglomerative cluster analysis including the six CSF APOs was carried out. Among non-demented older adults, we identified two clusters. Compare …with the first cluster, the second cluster had higher levels of APOs in CSF. Additionally, the second cluster showed a more benign disease course, including slower cognitive decline and slower p-tau accumulation in CSF. Our data highlight the importance of APOs in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, apolipoproteins, cluster analysis, cognitive decline

DOI: 10.3233/JAD-190314

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 413-423, 2019

Authors: Liu, Xiaoguang | Hebron, Michaeline L. | Mulki, Sanjana | Wang, Chen | Lekah, Elizabeth | Ferrante, Dalila | Shi, Wangke | Kurd-Misto, Bahjat | Moussa, Charbel

Article Type: Research Article

Abstract: Ubiquitin Specific Protease-13 (USP13) is a de-ubiquinating enzyme that regulates protein ubiquitination and clearance. The role of USP13 is largely unknown in neurodegeneration. In this study we aim to demonstrate whether tau accumulation and/or clearance depends on ubiquitination/de-ubiquitination via USP-13. We used transgenic animal models of human amyloid precursor protein (APP) or P301L tau mutations and genetically knocked-down USP13 expression via shRNA to determine USP13 effects on tau ubiquitination and levels. We found a two-fold increase of USP13 levels in postmortem Alzheimer’s disease (AD) brains. USP13 knockdown significantly increased the activity of the 20S proteasome and reduced the levels of …hyper-phosphorylated tau (p-tau) in primary cortical neurons. USP13 knockdown also reduced the levels of amyloid and increased p-tau ubiquitination and clearance in transgenic animal models that overexpress murine tau as a result of the expression of familial APP mutations (TgAPP) and the human mutant P301L tau (rTg4510), respectively. Clearance of p-tau appears to be mediated by autophagy in these animal models. Taken together, these data suggest that USP13 knockdown reduces p-tau accumulation via regulation of ubiquitination/de-ubiquitination and mediates its clearance via autophagy and/or the proteasome. These results suggest that USP13 inhibition may be a therapeutic strategy to reduce accumulation of plaques and toxic p-tau in AD and human tauopathies. Show more

Keywords: Alzheimer’s disease, amyloid, tau, ubiquitin, USP13

DOI: 10.3233/JAD-190635

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 425-441, 2019

Authors: Chen, Guanqun | Yang, Kun | Du, Wenying | Hu, Xiaochen | Han, Ying

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) refers to the self-perception of cognitive decline among cognitively normal elderly individuals. SCD related worry confers a higher risk of developing cognitive decline. However, the clinical characteristics of SCD patients with worry are not clear. Objective: To explore the clinical characteristics of SCD patients with worry. Methods: A cross-sectional study was carried out, with 270 consecutive participants of the Sino Longitudinal Study on Cognitive Decline (SILCODE) study. Participants were classified as normal controls (n  = 36), SCD patients without worry (n  = 91), or SCD patients with worry (n  = 143) and were comprehensively …compared on 1) their self-perception of cognitive decline, 2) multiple cognitive domains, 3) neuropsychiatric symptoms, and 4) sleep status. Results: SCD patients with worry had significantly more self-perception of cognitive decline (p  < 0.001); increased depression (p  < 0.001) and anxiety (p  < 0.001); decreased sleep quality (p  < 0.001), sleep latency (p  < 0.05), sleep time (p  < 0.01), and sleep efficiency (p  < 0.05); more sleep disorders (p  < 0.05) and daytime dysfunction (p  < 0.05); and a higher global score on the Pittsburgh Sleep Quality Index (p  < 0.001) than normal controls. Although there was a significant increase only in self-perception of cognitive decline (p  < 0.001), anxiety (p  < 0.001), and Pittsburgh Sleep Quality Index scores (p  < 0.05), the severity of the increase in those without worry was between that in SCD patients with worry and normal controls. Conclusion: Our findings show that participants who had SCD with worry showed distinct clinical characteristics compared with normal controls and SCD patients without worry, which could be useful for understanding the higher risk in SCD patients with worry of subsequently developing Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, clinical characteristic, neuropsychiatric symptoms, prevention trials, sleep disorders, subjective cognitive decline, subjective cognitive decline questionnaire

DOI: 10.3233/JAD-190501

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 443-454, 2019

Authors: Teipel, Stefan J. | Kuper-Smith, Jan O. | Bartels, Claudia | Brosseron, Frederic | Buchmann, Martina | Buerger, Katharina | Catak, Cihan | Janowitz, Daniel | Dechent, Peter | Dobisch, Laura | Ertl-Wagner, Birgit | Fließbach, Klaus | Haynes, John-Dylan | Heneka, Michael T. | Kilimann, Ingo | Laske, Christoph | Li, Siyao | Menne, Felix | Metzger, Coraline D. | Priller, Josef | Pross, Verena | Ramirez, Alfredo | Scheffler, Klaus | Schneider, Anja | Spottke, Annika | Spruth, Eike J. | Wagner, Michael | Wiltfang, Jens | Wolfsgruber, Steffen | Düzel, Emrah | Jessen, Frank | Dyrba, Martin | the DELCODE study group

Article Type: Research Article

Abstract: Diffusion changes as determined by diffusion tensor imaging are potential indicators of microstructural lesions in people with mild cognitive impairment (MCI), prodromal Alzheimer’s disease (AD), and AD dementia. Here we extended the scope of analysis toward subjective cognitive complaints as a pre-MCI at risk stage of AD. In a cohort of 271 participants of the prospective DELCODE study, including 93 healthy controls and 98 subjective cognitive decline (SCD), 45 MCI, and 35 AD dementia cases, we found reductions of fiber tract integrity in limbic and association fiber tracts in MCI and AD dementia compared with controls in a tract-based analysis …(p  < 0.05, family wise error corrected). In contrast, people with SCD showed spatially restricted white matter alterations only for the mode of anisotropy and only at an uncorrected level of significance. DTI parameters yielded a high cross-validated diagnostic accuracy of almost 80% for the clinical diagnosis of MCI and the discrimination of Aβ positive MCI cases from Aβ negative controls. In contrast, DTI parameters reached only random level accuracy for the discrimination between Aβ positive SCD and control cases from Aβ negative controls. These findings suggest that in prodromal stages of AD, such as in Aβ positive MCI, multicenter DTI with prospectively harmonized acquisition parameters yields diagnostic accuracy meeting the criteria for a useful biomarker. In contrast, automated tract-based analysis of DTI parameters is not useful for the identification of preclinical AD, including Aβ positive SCD and control cases. Show more

Keywords: amyloid, anisotropy, cerebral white matter, cognition, diagnosis, diffusion tensor imaging, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-190446

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 455-465, 2019

Authors: Tian, Jing | Wang, Tienju | Wang, Qi | Guo, Lan | Du, Heng

Article Type: Research Article

Abstract: Hippocampal lesions including synaptic injury, neuroinflammation, and impaired neurogenesis are featured pathology closely associated with neuronal stress and cognitive impairment in Alzheimer’s disease (AD). Previous studies suggest that ghrelin and its receptor, growth hormone secretagogue receptor 1α (GHSR1α ), promote hippocampal synaptic function and neurogenesis. GHSR1α activation thus holds the potential to be a therapeutic avenue for the treatment of hippocampal pathology in AD; however, a comprehensive study on the preventive effect of MK0677 on hippocampal lesions in AD-related conditions is still lacking. In this study, we treated a transgenic mouse model of AD-like amyloidosis (5xFAD mice) at …the asymptomatic stage with MK0677, a potent ghrelin mimetic. We found that MK0677 fostered hippocampal neurogenesis in 5xFAD mice but observed little preventive function with regards to the development of hippocampal amyloid-β (Aβ) deposition, synaptic loss, microglial activation, or cognitive impairment. Furthermore, MK0677 at a dose of 3 mg/kg significantly increased 5xFAD mouse mortality. Despite enhanced hippocampal neurogenesis, MK0677 treatment has little beneficial effect to prevent hippocampal lesions or cognitive deficits against Aβ toxicity. This study, together with a failed large-scale clinical trial, suggests the ineffectiveness of MK0677 alone for AD prevention and treatment. Show more

Keywords: Alzheimer’s disease, amyloid-β, growth hormone secretagogue receptor 1α, hippocampus, MK0677

DOI: 10.3233/JAD-190779

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 467-478, 2019