Journal of Alzheimer's Disease - Volume 70, issue 1

Authors: Blanken, Anna E. | Dutt, Shubir | Li, Yanrong | Nation, Daniel A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Clinical-pathological Alzheimer’s disease (AD) subtypes may help distill heterogeneity in patient presentation. To date, no studies have utilized neuropsychological and biological markers to identify preclinical subtypes with longitudinal stability. Objective: The objective of this study was to empirically derive AD endophenotypes using a combination of cognitive and biological markers. Methods: Hierarchical cluster analysis grouped dementia-free older adults using memory, executive and language abilities, and cerebrospinal fluid amyloid-β and phosphorylated tau. Brain volume differences, neuropsychological trajectory, and progression to dementia were compared, controlling for age, gender, education, and apolipoprotein E4 (ApoE4 ). Results: Subgroups …included asymptomatic-normal (n  = 653) with unimpaired cognition and subthreshold biomarkers, typical AD (TAD; n  = 191) showing marked memory decline, high ApoE4 rates and abnormal biomarkers, and atypical AD (AAD; n  = 132) with widespread cognitive decline, intermediate biomarker levels, older age, less education and more white matter lesions. Cognitive profiles showed longitudinal stability with corresponding patterns of cortical atrophy, despite nearly identical rates of progression to AD dementia. Conclusion: Two clinical-pathological AD subtypes are identified with potential implications for preventative efforts. Show more

Keywords: Alzheimer’s disease, atypical AD, cluster analysis, heterogeneity, neuroimaging

DOI: 10.3233/JAD-190230

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 227-239, 2019

Authors: Vorobyov, Vasily | Bakharev, Boris | Medvinskaya, Natalia | Nesterova, Inna | Samokhin, Alexander | Deev, Alexander | Tatarnikova, Olga | Ustyugov, Aleksey A. | Sengpiel, Frank | Bobkova, Natalia

Article Type: Research Article

Abstract: Cognitive malfunction, synaptic dysfunction, and disconnections in neural networks are core deficits in Alzheimer’s disease (AD). 5xFAD mice, a transgenic model of AD, are characterized by an enhanced level of amyloid-β and abnormal neurotransmission. The dopaminergic (DA) system has been shown to be involved in amyloid-β transformations and neuronal plasticity; however, its role in functional network changes in familial AD still remains unclear. In 5xFAD and non-transgenic freely moving mice, electroencephalograms (EEGs) were simultaneously recorded from the secondary motor cortex (MC), superficial layers of the hippocampal CA1 area (HPC), substantia nigra (SN), and ventral tegmental area (VTA). EEGs and their …frequency spectra were analyzed before and after systemic injection of a DA receptor agonist, apomorphine (APO). In the baseline EEG from MC and HPC of 5xFAD mice, delta and alpha oscillations were enhanced and beta activity was attenuated, compared to control mice. In VTA and SN of 5xFAD mice, delta -theta activity was decreased and beta oscillations dominated. In control mice, APO suppressed delta activity in VTA to a higher extent than in MC, whereas in 5xFAD mice, this difference was eliminated due to attenuation of the delta suppression in VTA. APO increased beta activity in MC of mice from both groups while significant beta suppression was observed in VTA of 5xFAD mice. These mice were characterized by significant decrease of tyrosine hydroxylase immunopositive cells in both VTA and SN and of DA transporter in MC and hippocampal dentate gyrus. We suggest that the EEG modifications observed in 5xFAD mice are associated with alterations in dopaminergic transmission, resulting in adaptive changes in the cerebral networks in the course of familial AD development. Show more

Keywords: Dopamine transporter, electroencephalogram, frequency spectrum, hippocampus, secondary motor cortex, substantia nigra, ventral tegmental area

DOI: 10.3233/JAD-181246

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 241-256, 2019

Authors: Niedźwieńska, Agnieszka | Kvavilashvili, Lia

Article Type: Research Article

Abstract: Identifying people with amnestic mild cognitive impairment (aMCI), who are at increased risk of developing Alzheimer’s disease, is important for improving early disease management and care. Although self- or informant-reported memory problems constitute one of the diagnostic criteria of aMCI, there is currently little empirical knowledge about the frequency and nature of everyday memory failures in aMCI compared to age-matched healthy controls. Consequently, clinicians rely on their personal judgements when assessing the seriousness of reported memory failures. To address this gap in our knowledge, 32 aMCI participants and 38 healthy controls recorded their everyday memory failures as and when they …occurred during a 7-day period, in a portable diary-booklet, by filling in a short questionnaire on a diary page. Descriptions of memory failures were coded into several subcategories of retrospective memory, prospective memory, and absent-minded failures. Results showed that a total number of recorded failures was significantly higher in participants with aMCI than controls. This group difference was mainly due to aMCI participants recording a higher number of retrospective memory failures, while groups did not differ in the number of prospective memory and absent-minded failures. Additionally, while certain types of failures (i.e., forgetting appointments and well-learned procedures) were recorded by a proportion of aMCI patients, they were never reported in a control group. Overall compliance rates were high and did not differ across the groups, suggesting that a structured diary method is feasible to use with aMCI patients, and can provide useful information about everyday memory functioning in this population. Show more

Keywords: Alzheimer’s disease, dementia, diary, memory, mild cognitive impairment

DOI: 10.3233/JAD-190219

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 257-275, 2019

Authors: Bergeron, Michael F. | Landset, Sara | Tarpin-Bernard, Franck | Ashford, Curtis B. | Khoshgoftaar, Taghi M. | Ashford, J. Wesson

Article Type: Research Article

Abstract: Background: Memory dysfunction is characteristic of aging and often attributed to Alzheimer’s disease (AD). An easily administered tool for preliminary assessment of memory function and early AD detection would be integral in improving patient management. Objective: Our primary aim was to utilize machine learning in determining initial viable models to serve as complementary instruments in demonstrating efficacy of the MemTrax online Continuous Recognition Tasks (M-CRT) test for episodic-memory screening and assessing cognitive impairment. Methods: We used an existing dataset subset (n  = 18,395) of demographic information, general health screening questions (addressing memory, sleep quality, medications, and medical …conditions affecting thinking), and test results from a convenience sample of adults who took the M-CRT test. M-CRT performance and participant features were used as independent attributes: true positive/negative, percent responses/correct, response time, age, sex, and recent alcohol consumption. For predictive modeling, we used demographic information and test scores to predict binary classification of the health-related questions (yes/no) and general health status (healthy/unhealthy), based on the screening questions. Results: ANOVA revealed significant differences among HealthQScore groups for response time true positive (p  = 0.000) and true positive (p  = 0.020), but none for true negative (p  = 0.0551). Both % responses and % correct had significant differences (p  = 0.026 and p  = 0.037, respectively). Logistic regression was generally the top-performing learner with moderately robust prediction performance (AUC) for HealthQScore (0.648–0.680) and selected general health questions (0.713–0.769). Conclusion: Our novel application of supervised machine learning and predictive modeling helps to demonstrate and validate cross-sectional utility of MemTrax in assessing early-stage cognitive impairment and general screening for AD. Show more

Keywords: Aging, Alzheimer’s disease, dementia, mass screening

DOI: 10.3233/JAD-190165

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 277-286, 2019

Authors: Anastasio, Thomas J.

Article Type: Research Article

Abstract: Identification of drug combinations that could be effective in Alzheimer’s disease treatment is made difficult by the sheer number of possible combinations. This analysis identifies as potentially therapeutic those drug combinations that rank highest when their efficacy is determined jointly from two independent data sources. Estimates of the efficacy of the same drug combinations were derived from a clinical dataset on cognitively impaired elderly participants and from pre-clinical data, in the form of a computational model of neuroinflammation. Linear regression was used to show that the two sets of estimates were correlated, and to rule out confounds. The ten highest …ranking, jointly determined drug combinations most frequently consisted of COX2 inhibitors and aspirin, along with various antihypertensive medications. Ten combinations of from five to nine drugs, and the three-drug combination of a COX2 inhibitor, aspirin, and a calcium-channel blocker, are discussed as candidates for consideration in future pre-clinical and clinical studies. Show more

Keywords: Combination therapy, computational modeling, data mining, deep learning, machine learning, microglia, neural network, neuroinflammation, polypharmacy, research database

DOI: 10.3233/JAD-190144

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 287-302, 2019

Authors: Huang, Xi | Wang, Chenchen | Tian, Sai | Huang, Rong | Guo, Dan | Zhang, Haoqiang | Shi, Jijing | Wang, Shaohua

Article Type: Research Article

Abstract: Background: In addition to glucose metabolism, adipocytokine Nicotinamide phosphoribosyltransferase (Nampt) has been proposed as a multifunctional protein involved in insulin resistance. Insulin resistance always occurs before the onset of type 2 diabetes mellitus (T2DM) and damages the cognition of T2DM patients very early. Objective: We aimed to investigate the role and potential clinical value of Nampt in early cognitive decline of T2DM. Methods: A total of 195 Chinese T2DM patients were enrolled and divided into a mild cognition impairment (MCI) group and a healthy cognition group according to Montreal Cognitive Assessment (MoCA) score. Their cognitive function …was extensively assessed. The plasma level of Nampt was measured via enzyme-linked immunosorbent assay. Results: In the MCI group (n  = 78, MoCA < 26), the plasma level of Nampt was significantly higher than the controls (p  < 0.01). After adjusting for age, sex, and level of education, Nampt levels were negatively associated with most of the cognitive domains forecasting hypomnesia (all p  < 0.007). Nevertheless, hierarchical regression analysis further revealed that Nampt was an independent risk factor of MCI in Chinese T2DM patients (all p  < 0.05), including Logic Memory Test (β= –0.31, p  < 0.01), Auditory Verbal Learning Test delayed recall (β= –0.26, p  < 0.01), and so on, which represent memory function. Correlation analysis showed that Nampt related to insulin resistance (HOMA-IR), glycosylated hemoglobin (HbA1c), and lipid levels (all p  < 0.05). Conclusions: We found that higher plasma level of Nampt presages memory dysfunction in MCI in Chinese T2DM patients. Further studies are necessary to confirm its scanning and prognosis prediction value of the disease clinically. Show more

Keywords: Adipocytokine, Alzheimer’s disease, hypomnesia, mild cognition impairment, nicotinamide phosphoribosyltransferase, type 2 diabetes

DOI: 10.3233/JAD-190269

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 303-314, 2019