Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Li, Dongxue | Liu, Yuancheng | Zeng, Xianchun | Xiong, Zhenliang | Yao, Yuanrong | Liang, Daiyi | Qu, Hao | Xiang, Hui | Yang, Zhenggui | Nie, Lisha | Wu, Pu-Yeh | Wang, Rongpin

Article Type: Research Article

Abstract: Background: Advanced Alzheimer’s disease (AD) has no effective treatment, and identifying early diagnosis markers can provide a time window for treatment. Objective: To quantify the changes in cerebral blood flow (CBF) and iron deposition during progression of AD. Methods: 94 subjects underwent brain imaging on a 3.0-T MRI scanner with techniques of three-dimensional arterial spin labeling (3D-ASL) and quantitative susceptibility mapping (QSM). The subjects included 22 patients with probable AD, 22 patients with mild cognitive impairment (MCI), 25 patients with subjective cognitive decline (SCD), and 25 normal controls (NC). The CBF and QSM values were obtained …using a standardized brain region method based on the Brainnetome Atlas. The differences in CBF and QSM values were analyzed between and within groups using variance analysis and correlation analysis. Results: CBF and QSM identified several abnormal brain regions of interest (ROIs) at different stages of AD (p  < 0.05). Regionally, the CBF values in several ROIs of the AD and MCI subjects were lower than for NC subjects (p  < 0.001). Higher QSM values were observed in the globus pallidus. The CBF and QSM values in multiple ROI were negatively correlated, while the putamen was the common ROI of the three study groups (p  < 0.05). The CBF and QSM values in hippocampus were cross-correlated with scale scores during the progression of AD (p  < 0.05). Conclusion: Iron deposition in the basal ganglia and reduction in blood perfusion in multiple regions existed during the progression of AD. The QSM values in putamen can be used as an imaging biomarker for early diagnosis of AD. Show more

Keywords: Alzheimer’s disease, Brainnetome Atlas, 3D-arterial spin labeling, quantitative susceptibility mapping

DOI: 10.3233/JAD-200843

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Graves, Lisa V. | Edmonds, Emily C. | Thomas, Kelsey R. | Weigand, Alexandra J. | Cooper, Shanna | Bondi, Mark W.

Article Type: Research Article

Abstract: Background: Research suggests that actuarial neuropsychological criteria improve the accuracy of mild cognitive impairment (MCI) diagnoses relative to conventional diagnostic methods. Objective: We sought to examine the utility of actuarial criteria relative to consensus diagnostic methods used in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS), and more broadly across the continuum of normal aging, MCI, and dementia. Methods: We compared rates of cognitively normal (CN), MCI, and dementia diagnoses at baseline using actuarial versus consensus diagnostic methods in 1524 individuals from the NACC UDS. Results: Approximately one-third (33.59%) of individuals diagnosed …as CN and more than one-fifth (22.03%) diagnosed with dementia based on consensus methods, met actuarial criteria for MCI. Many participants diagnosed with MCI via consensus methods also appeared to represent possible diagnostic errors. Notably, the CNa /CNc group (i.e., participants diagnosed as CN based on both actuarial [a ] and consensus [c ] criteria) had a lower proportion of apolipoprotein E ɛ 4 carriers than the MCIa /MCIc group, which in turn had a lower proportion of ɛ 4 carriers than the dementia (Dem)a /Demc group. Proportions of ɛ 4 carriers were comparable between the CNa /CNc and CNa /MCIc , MCIa /MCIc and MCIa /CNc , MCIa /MCIc and MCIa /Demc , and Dema /Demc and Dema /MCIc groups. These results were largely consistent with diagnostic agreement/discrepancy group comparisons on neuropsychological performance. Conclusion: The present results extend previous findings and suggest that actuarial neuropsychological criteria may enhance diagnostic accuracy relative to consensus methods, and across the wider continuum of normal aging, MCI, and dementia. Findings have implications for both clinical practice and research. Show more

Keywords: Alzheimer’s disease, dementia, diagnostic errors, mild cognitive impairment, misdiagnosis, neuropsychology

DOI: 10.3233/JAD-200778

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Talan, Jamie

Article Type: Obituary

DOI: 10.3233/JAD-201108

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2020

Authors: Zygouris, Stelios | Iliadou, Paraskevi | Lazarou, Eftychia | Giakoumis, Dimitrios | Votis, Konstantinos | Alexiadis, Anastasios | Triantafyllidis, Andreas | Segkouli, Sofia | Tzovaras, Dimitrios | Tsiatsos, Thrasyvoulos | Papagianopoulos, Sotirios | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: Literature supports the use of serious games and virtual environments to assess cognitive functions and detect cognitive decline. This promising assessment method, however, has not yet been translated into self-administered screening instruments for pre-clinical dementia. Objective: The aim of this study is to assess the performance of a novel self-administered serious game-based test, namely the Virtual Supermarket Test (VST), in detecting mild cognitive impairment (MCI) in a sample of older adults with subjective memory complaints (SMC), in comparison with two well-established screening instruments, the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). Methods: …Two groups, one of healthy older adults with SMC (N = 48) and one of MCI patients (N = 47) were recruited from day centers for cognitive disorders and administered the VST, the MoCA, the MMSE, and an extended pencil and paper neuropsychological test battery. Results: The VST displayed a correct classification rate (CCR) of 81.91% when differentiating between MCI patients and older adults with SMC, while the MoCA displayed of CCR of 72.04% and the MMSE displayed a CCR of 64.89%. Conclusion: The three instruments assessed in this study displayed significantly different performances in differentiating between healthy older adults with SMC and MCI patients. The VST displayed a good CCR, while the MoCA displayed an average CCR and the MMSE displayed a poor CCR. The VST appears to be a robust tool for detecting MCI in a population of older adults with SMC. Show more

Keywords: Aging, Alzheimer’s disease, computers, dementia, diagnosis, memory disorders, mild cognitive impairment, serious games, subjective cognitive decline, user-computer interface

DOI: 10.3233/JAD-200880

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Zhang, Rui-Qi | Chen, Shi-Dong | Shen, Xue-Ning | Yang, Yu-Xiang | Lu, Jia-Ying | Cui, Mei | Zuo, Chuan-Tao | Dong, Qiang | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The recent developed PET ligands for amyloid-β (Aβ) and tau allow these two neuropathological hallmarks of Alzheimer’s disease (AD) to be mapped and quantified in vivo and to be examined in relation to cognition. Objective: To assess the associations among Aβ, tau, and cognition in non-demented subjects. Methods: Three hundred eighty-nine elderly participants without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent tau and amyloid PET scans. Cross-sectional comparisons and longitudinal analyses were used to evaluate the relationship between Aβ and tau accumulation. The correlations between biomarkers of both pathologies and performance in memory …and executive function were measured. Results: Increased amyloid-PET retention was associated with greater tau-PET retention in widespread cortices. We observed a significant tau increase in the temporal composite regions of interest over 24 months in Aβ+ but not Aβ– subjects. Finally, tau-PET retention but not amyloid-PET retention significantly explained the variance in memory and executive function. Higher level of tau was associated with greater longitudinal memory decline. Conclusion: These findings suggested PET-detectable Aβ plaque pathology may be a necessary antecedent for tau-PET signal elevation. Greater tau-PET retention may demonstrate poorer cognition and predict prospective memory decline in non-demented AD subjects. Show more

Keywords: Alzheimer’s disease, amyloid-PET, cognitive impairment, tau-PET

DOI: 10.3233/JAD-200526

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Abdelnour, Carla | Esteban de Antonio, Ester | Pérez-Cordón, Alba | Lafuente, Asunción | Buendía, Mar | Pancho, Ana | Jofresa, Sara | Aguilera, Nuria | Ibarria, Marta | Cuevas, Rosario | Cañada, Laia | Calvet, Anna | Diego, Susana | González-Pérez, Antonio | Orellana, Adela | Montrreal, Laura | de Jorge, Laura | Marquié, Marta | Benaque, Alba | Gurruchaga, Miren | Tárraga, Lluís | Ruiz, Agustín | Boada, Mercè | for the Research Center and Memory Clinic, Fundació ACE

Collaborators: Isabel, Hernández | Montserrat, Alegret | Pilar, Cañabate | Isabel, Rodríguez | Maitee, Rosende-Roca | Juan Pablo, Tartari | Rogelio, López | Silvia, Gil | Liliana, Vargas | Ana, Mauleón | Ana, Espinosa | Gemma, Ortega | Angela, Sanabria | Emilio, Alarcón | Mariola, Moreno | Silvia, Preckler | Natalia, Roberto | Sergi, Valero | Itziar, de Rojas | Sonia, Moreno-Grau | Elvira, Martín

Article Type: Research Article

Abstract: Background: The COVID-19 pandemic has brought great disruption to health systems worldwide. This affected ongoing clinical research, particularly among those most vulnerable to the pandemic, like dementia patients. Fundació ACE is a research center and memory clinic based in Barcelona, Spain, one of the hardest-hit countries. Objective: To describe the ad-hoc strategic plan developed to cope with this crisis and to share its outcomes. Methods: We describe participants’ clinical and demographic features. Additionally, we explain our strategic plan aimed at minimizing the impact on clinical trial research activities, which included SARS-CoV-2 RT-PCR and IgG serological tests …to all participants and personnel. The outcomes of the plan are described in terms of observed safety events and drop-outs during the study period. Results: A total of 130 patients were participating in 16 active clinical trials in Fundació ACE when the lockdown was established. During the confinement, we performed 1018 calls to the participants, which led to identify adverse events in 26 and COVID-19 symptoms in 6. A total of 83 patients (64%) could restart on-site visits as early as May 11, 2020. All SARS-CoV-2 RT-PCR diagnostic tests performed before on-site visits were negative and only three IgG serological tests were positive. Throughout the study period, we only observed one drop-out, due to an adverse event unrelated to COVID-19. Discussion: The plan implemented by Fundació ACE was able to preserve safety and integrity of ongoing clinical trials. We must use the lessons learned from the pandemic and design crisis-proof protocols for clinical trials. Show more

Keywords: Alzheimer’s disease, clinical trials, coronavirus, pandemics, telemedicine

DOI: 10.3233/JAD-200750

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Moreira, Natália Chermont dos Santos | Lima, Jéssica Ellen Barbosa de Freitas | Chierrito, Talita Perez Cantuaria | Carvalho, Ivone | Sakamoto-Hojo, Elza Tiemi

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by a progressive loss of episodic memory associated with amyloid-β peptide aggregation and the abnormal phosphorylation of the tau protein, leading to the loss of cholinergic function. Acetylcholinesterase (AChE) inhibitors are the main class of drugs used in AD therapy. Objective: The aim of the current study was to evaluate the potential of two tacrine-donepezil hybrid molecules (TA8Amino and TAHB3), which are AChE inhibitors, to induce neurodifferentiation and neuritogenesis in SH-SY5Y cells. Methods: The experiments were carried out to characterize neurodifferentiation, cellular changes related to responses to oxidative stress and …pathways of cell survival in response to drug treatments. Results: The results indicated that the compounds did not present cytotoxic effects in SH-SY5Y or HepG2 cells. TA8Amino and TAHB3 induced neurodifferentiation and neuritogenesis in SH-SY5Y cells. These cells showed increased levels of intracellular and mitochondrial reactive oxygen species; the induction of oxidative stress was also demonstrated by an increase in SOD1 expression in TA8Amino and TAHB3-treated cells. Cells treated with the compounds showed an increase in PTEN(Ser380/Thr382/383) and AKT(Ser473) expression, suggesting the involvement of the AKT pathway. Conclusion: Our results demonstrated that TA8Amino and TAHB3 present advantages as potential drugs for AD therapy and that they are capable of inducing neurodifferentiation and neuritogenesis. Show more

Keywords: Acetylcholinesterase inhibitors, AKT pathway, Alzheimer’s disease, neuronal differentiation, oxidative stress, SH-SY5Y cells

DOI: 10.3233/JAD-200425

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Katherine Blujus, Jenna | Elizabeth Korthauer, Laura | Awe, Elizabeth | Frahmand, Marijam | Driscoll, Ira

Article Type: Research Article

Abstract: Background: It is critical to identify individuals at risk for Alzheimer’s disease (AD) earlier in the disease time course, such as middle age and preferably well prior to the onset of clinical symptoms, when intervention efforts may be more successful. Genome-wide association and candidate gene studies have identified single nucleotide polymorphisms (SNPs) in APOE , CLU , CR1 , PICALM , and SORL1 that confer increased risk of AD. Objective: In the current study, we investigated the associations between SNPs in these genes and resting-state functional connectivity within the default mode network (DMN), frontoparietal control network (FPN), …and executive control network (ECN) in healthy, non-demented middle-aged adults (age 40 –60; N = 123; 74 females). Methods: Resting state networks of interest were identified through independent components analysis using a template-matching procedure and individual spatial maps and time courses were extracted using dual regression. Results: Within the posterior DMN, functional connectivity was associated with CR1 rs1408077 and CLU rs9331888 polymorphisms (p s <  0.05). FPN connectivity was associated with CR1 rs1408077, CLU rs1136000, SORL1 rs641120, and SORL1 rs689021 (ps <  0.05). Functional connectivity within the ECN was associated with the CLU rs11136000 (p  <  0.05). There were no APOE- or PICALM-related differences in any of the networks investigated (ps >  0.05). Conclusion: This is the first demonstration of the relationship between intrinsic network connectivity and AD risk alleles in CLU , CR1 , and SORL1 in healthy, middle-aged adults. These SNPs should be considered in future investigations aimed at identifying potential preclinical biomarkers for AD. Show more

Keywords: Aging, Alzheimer’s disease, middle aged, neuroimaging, single nucleotide polymorphism

DOI: 10.3233/JAD-200444

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Xia, Ying | Yassi, Nawaf | Raniga, Parnesh | Bourgeat, Pierrick | Desmond, Patricia | Doecke, James | Ames, David | Laws, Simon M. | Fowler, Christopher | Rainey-Smith, Stephanie R. | Martins, Ralph | Maruff, Paul | Villemagne, Victor L. | Masters, Colin L. | Rowe, Christopher C. | Fripp, Jurgen | Salvado, Olivier | for the AIBL Research Group

Article Type: Research Article

Abstract: Background: Cerebrovascular disease often coexists with Alzheimer’s disease (AD). While both diseases share common risk factors, their interrelationship remains unclear. Increasing the understanding of how cerebrovascular changes interact with AD is essential to develop therapeutic strategies and refine biomarkers for early diagnosis. Objective: We investigate the prevalence and risk factors for the comorbidity of amyloid-β (Aβ ) and cerebrovascular disease in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing, and further examine their cross-sectional association. Methods: A total of 598 participants (422 cognitively normal, 89 with mild cognitive impairment, 87 with AD) underwent positron …emission tomography and structural magnetic resonance imaging for assessment of Aβ deposition and cerebrovascular disease. Individuals were categorized based on the comorbidity status of Aβ and cerebrovascular disease (V) as Aβ –V–, Aβ –V+, Aβ +V–, or Aβ +V+. Results: Advancing age was associated with greater likelihood of cerebrovascular disease, high Aβ load and their comorbidity. Apolipoprotein E ɛ 4 carriage was only associated with Aβ positivity. Greater total and regional WMH burden were observed in participants with AD. However, no association were observed between Aβ and WMH measures after stratification by clinical classification, suggesting that the observed association between AD and cerebrovascular disease was driven by the common risk factor of age. Conclusion: Our observations demonstrate common comorbid condition of Aβ and cerebrovascular disease in later life. While our study did not demonstrate a convincing cross-sectional association between Aβ and WMH burden, future longitudinal studies are required to further confirm this. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrovascular disease, white matter hyperintensities

DOI: 10.3233/JAD-200419

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Asken, Breton M. | Elahi, Fanny M. | La Joie, Renaud | Strom, Amelia | Staffaroni, Adam M. | Lindbergh, Cutter A. | Apple, Alexandra C. | You, Michelle | Weiner-Light, Sophia | Brathaban, Nivetha | Fernandes, Nicole | Karydas, Anna | Wang, Paul | Rojas, Julio C. | Boxer, Adam L. | Miller, Bruce L. | Rabinovici, Gil D. | Kramer, Joel H. | Casaletto, Kaitlin B.

Article Type: Research Article

Abstract: Background: Measuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-β (Aβ) may shed light on astrocytic changes in aging and Alzheimer’s disease (AD). Objective: To examine associations between plasma GFAP and cortical Aβ deposition in older adults across the typical aging-to-AD dementia spectrum. Methods: We studied two independent samples from UCSF (Cohort 1, N = 50; Cohort 2, N = 37) covering the spectra of clinical severity (CDR Sum of Boxes; CDR-SB) and Aβ-PET burden. Aβ-PET was completed with either florbetapir or Pittsburgh Compound B and standardized uptake value ratios were converted to the Centiloid (CL) scale for analyses. …All participants with CDR-SB >  0 were Aβ-PET positive, while clinically normal participants (CDR-SB = 0) were a mix of Aβ-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aβ-PET, and clinical severity. Results: In both cohorts, plasma GFAP increased linearly with Aβ-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aβ-PET burden, the association between Aβ and GFAP became curvilinear (inverted U-shape; quadratic model R2 change = 0.165, p  = 0.009), and Aβ-PET interacted with CDR-SB (R2 change = 0.164, p  = 0.007): older adults with intermediate functional impairment (CDR-SB = 0.5–4.0) showed a weak (negative) association between Aβ-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB >  4.0) showed a strong, negative association of higher Aβ-PET CLs with lower plasma GFAP. Conclusion: The relationship between astrocytic integrity and cortical Aβ may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages. Show more

Keywords: Alzheimer’s disease, amyloid, astrocyte, biomarker, glial fibrillary acidic protein, plasma

DOI: 10.3233/JAD-200755

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020