Journal of Alzheimer's Disease - Volume 87, issue 4

Authors: Chen, Durong | Yi, Fuliang | Qin, Yao | Zhang, Jiajia | Ge, Xiaoyan | Han, Hongjuan | Cui, Jing | Bai, Wenlin | Wu, Yan | Yu, Hongmei | the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a severe health problem. Challenges still remain in early diagnosis. Objective: The objective of this study was to build a Stacking framework for multi-classification of AD by a combination of neuroimaging and clinical features to improve the performance. Methods: The data we used were from the Alzheimer’s Disease Neuroimaging Initiative database with a total of 493 subjects, including 125 normal control (NC), 121 early mild cognitive impairment, 109 late mild cognitive impairment (LMCI), and 138 AD. We selected structural magnetic resonance imaging (sMRI) feature by voting strategy. The imaging feature, demographic …information, Mini-Mental State Examination, and Alzheimer’s Disease Assessment Scale-Cognitive Subscale were combined together as classification features. We proposed a two-layer Stacking ensemble framework to classify four types of people. The first layer represented support vector machine, random forest, adaptive boosting, and gradient boosting decision tree; the second layer was a logistic regression classifier. Additionally, we analyzed performance of only sMRI feature and combined features and compared the proposed model with four base classifiers. Results: The Stacking model combined with sMRI and non-imaging features outshined four base classifiers with an average accuracy of 86.96%. Compared with using sMRI data alone, sMRI combined with non-imaging features significantly improved diagnostic accuracy, especially in NC versus LMCI. Conclusion: The Stacking framework we used can improve performance in diagnosis of AD using combined features. Show more

Keywords: Alzheimer’s disease, classification, ensemble learning, neuroimaging

DOI: 10.3233/JAD-215654

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1627-1636, 2022

Authors: Leng, Minmin | Sun, Yue | Chang, Hui | Wang, Zhiwen

Article Type: Research Article

Abstract: Background: Recognizing the correlations between care problems of people with dementia could help clinicians choose treatment methods because related symptom groups might respond to the same treatment intervention. Objective: This study aimed to evaluate the prevalence of various care problems in people with dementia and to explore the core care problems and correlations between care problems of people with dementia. Methods: This cross-sectional study recruited family caregivers of people with dementia through memory clinics and WeChat groups. Care problems of people with dementia were measured using a care problems evaluation sheet, which involved three aspects: daily …living care problems, behavioral and psychological symptoms, and safety risks. Clustering analysis of the care problems based on Kruskal’s minimum spanning tree (MST) algorithm was performed in the Jupyter Notebook software to explore the core care problems and their correlations. Results: A total of 687 carer-patient pairs were included in the analysis. In general, the prevalence of having difficulty in language performance, agitated behavior, and incidence of falls was relatively higher than other care problems in people with dementia, which distressed their family caregivers. Through clustering analysis, the 63 care problems were clustered into 7 clusters and 7 core care problems were identified. Conclusion: The prevalence of various care problems of people living with dementia in China was relatively high. The information regarding correlations in clusters among care problems will help practitioners and policymakers to identify the core care problems and optimize more rational treatments for people with dementia. Show more

Keywords: Caregivers, cluster analysis, dementia, patient care

DOI: 10.3233/JAD-215682

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1637-1646, 2022

Authors: Shaw, Benjamin C. | Snider, Henry C. | Turner, Andrew K. | Zajac, Diana J. | Simpson, James F. | Estus, Steven

Article Type: Research Article

Abstract: Background: Genetic variants in TREM2 are strongly associated with Alzheimer’s disease (AD) risk but alternative splicing in TREM2 transcripts has not been comprehensively described. Objective: Recognizing that alternative splice variants can result in reduced gene expression and/or altered function, we sought to fully characterize splice variation in TREM2 . Methods: Human anterior cingulate autopsy tissue from 61 donors was used for end-point and quantitative PCR and western blotting to identify and quantify novel TREM2 isoforms. Results: In addition to previously described transcripts lacking exon 3 or exon 4, or retaining …part of intron 3, we identified novel isoforms lacking exon 2, along with isoforms lacking multiple exons. Isoforms lacking exon 2 were predominant at approximately 10% of TREM2 mRNA in the brain. Expression of TREM2 and frequency of exon 2 skipping did not differ between AD samples and non-AD controls (p  = 0.1268 and p  = 0.4909, respectively). Further, these novel splice isoforms were also observed across multiple tissues with similar frequency (range 5.3 –13.0%). We found that the exon 2 skipped isoform D2-TREM2 is translated to protein and localizes similarly to full-length TREM2 protein, that both proteins are primarily retained in the Golgi complex, and that D2-TREM2 is expressed in AD and non-AD brain. Conclusion: Since the TREM2 ligand binding domain is encoded by exon 2, and skipping this exon retains reading frame while conserving localization, we hypothesize that D2-TREM2 acts as an inhibitor of TREM2 and targeting TREM2 splicing may be a novel therapeutic pathway for AD. Show more

Keywords: Alternative splicing, Alzheimer’s disease, colocalization, gene expression

DOI: 10.3233/JAD-215602

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1647-1657, 2022

Authors: Sarto, Jordi | Mayà, Gerard | Molina-Porcel, Laura | Balasa, Mircea | Gelpi, Ellen | Aldecoa, Iban | Borrego-Écija, Sergi | Contador, Jose | Ximelis, Teresa | Vergara, Miguel | Antonell, Anna | Sánchez-Valle, Raquel | Lladó, Albert

Article Type: Research Article

Abstract: Background: Early onset Alzheimer’s disease (EOAD) represents a diagnostic challenge and is associated with a high diagnostic delay and misdiagnosis. Objective: To describe clinical and pathological data from a pathologically confirmed EOAD cohort and evaluate evolving trends in clinical-pathological correlation accuracy. Methods: Retrospective review of clinical and neuropathological data of pathologically confirmed EOAD patients (age at onset [AAO] < 60). Comparison between two periods: 1994– 2009 and 2010– 2018. Results: Eighty brain donors were included. Mean AAO, age at death, and diagnostic delay was 55, 66, and 3 years, respectively. Twenty-nine percent had a nonamnestic presentation. …Sixteen percent were given a non-AD initial clinical diagnosis (initial misdiagnosis) and 14% received a final misdiagnosis. Nonamnestic presentation patients received more misdiagnoses than amnestic presentation ones (39% versus 7% and 39% versus 3.5%, on initial and final misdiagnosis, respectively). When comparing both time periods, a trend towards a higher diagnostic accuracy in the 2010– 2018 period was observed, mainly on initial misdiagnosis in nonamnestic presentation patients (53% versus 13%, p  = 0.069). Diagnostic delay was similar between both periods. Cerebral amyloid angiopathy (96%) and Lewy body co-pathology (55%) were very frequent, while limbic-predominant age-related TDP-43 encephalopathy pathologic changes were only present in 12.5%. Conclusion: In the last decade, there has been a trend towards improved diagnostic accuracy in EOAD, which might be explained by improved diagnostic criteria, increasing experience on EOAD and the beginning of the use of biomarkers, although diagnostic delay remains similar. Concomitant neuropathology was very frequent despite the relatively young age of brain donors. Show more

Keywords: Brain bank, clinical-pathological correlations, dementia clinical manifestations, early onset Alzheimer disease, neuropathology

DOI: 10.3233/JAD-220045

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1659-1669, 2022

Authors: Lio, Chit Tong | Kacprowski, Tim | Klaedtke, Maik | Jensen, Lars R. | Bouter, Yvonne | Bayer, Thomas A. | Kuss, Andreas W.

Article Type: Research Article

Abstract: Background: The Tg4-42 mouse model for sporadic Alzheimer’s disease (AD) has unique features, as the neuronal expression of wild type N-truncated Aβ4–42 induces an AD-typical neurological phenotype in the absence of plaques. It is one of the few models developing neuron death in the CA1 region of the hippocampus. As such, it could serve as a powerful tool for preclinical drug testing and identification of the underlying molecular pathways that drive the pathology of AD. Objective: The aim of this study was to use a differential co-expression analysis approach for analyzing a small RNA sequencing dataset from …a well-established murine model in order to identify potentially new players in the etiology of AD. Methods: To investigate small nucleolar RNAs in the hippocampus of Tg4-42 mice, we used RNA-Seq data from this particular tissue and, instead of analyzing the data at single gene level, employed differential co-expression analysis, which takes the comparison to gene pair level and thus affords a new angle to the interpretation of these data. Results: We identified two clusters of differentially correlated small RNAs, including Snord55, Snord57, Snord49a, Snord12, Snord38a, Snord99, Snord87, Mir1981, Mir106b, Mir30d, Mir598, and Mir99b. Interestingly, some of them have been reported to be functionally relevant in AD pathogenesis, as AD biomarkers, regulating tau phosphorylation, TGF-β receptor function or Aβ metabolism. Conclusion: The majority of snoRNAs for which our results suggest a potential role in the etiology of AD were so far not conspicuously implicated in the context of AD pathogenesis and could thus point towards interesting new avenues of research in this field. Show more

Keywords: Alzheimer’s disease, miRNA, NGS, RNA-Seq, small RNA, snoRNA, Tg4-42, transgenic mouse model

DOI: 10.3233/JAD-220110

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1671-1681, 2022

Authors: Webb, Katherine L. | Ryan, Joanne | Wolfe, Rory | Woods, Robyn L. | Shah, Raj C. | Murray, Anne M. | Orchard, Suzanne G. | Storey, Elsdon

Article Type: Research Article

Abstract: Background: Cognitive test-retest reliability measures can be used to evaluate meaningful changes in scores. Objective: This analysis aimed to develop a comprehensive set of test-retest reliability values and minimal detectable change (MDC) values for a cognitive battery for community-dwelling older individuals in Australia and the U.S., for use in clinical practice. Methods: Cognitive scores collected at baseline and year 1, in the ASPirin in Reducing Events in the Elderly clinical trial were used to calculate intraclass correlation coefficients (ICC) for four tests: Modified Mini-Mental State examination (3MS), Hopkins Verbal Learning Test-Revised (HVLT-R), single-letter Controlled Oral Word …Association Test (COWAT-F), and Symbol Digit Modalities Test (SDMT). 16,956 participants aged 70 years and over (65 years and over for U.S. minorities) were included. ICCs were used to calculate MDC values for eight education and ethno-racial subgroups. Results: All four cognitive tests had moderate (ICC > 0.5) to good (ICC > 0.7) test-retest reliability. ICCs ranged from 0.53 to 0.63 (3MS), 0.68 to 0.77 (SDMT), 0.56 to 0.64 (COWAT-F), 0.57 to 0.69 (HVLT-R total recall), and 0.57 to 0.70 (HVLT-R delayed recall) across the subgroups. MDC values ranged from 6.60 to 9.95 (3MS), 12.42 to 15.61 (SDMT), 6.34 to 8.34 (COWAT-F), 8.13 to 10.85 (HVLT-R total recall), and 4.00 to 5.62 (HVLT-R delayed recall). Conclusion: This large cohort of older individuals provides test-retest reliability and MDC values for four widely employed tests of cognitive function. These results can aid interpretation of cognitive scores and decline instead of relying on cross-sectional normative data alone. Show more

Keywords: Controlled oral word association test, hopkins verbal learning test-revised, minimal detectable change, modified mini-mental state examination, symbol digit modalities test, test-retest reliability

DOI: 10.3233/JAD-215564

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1683-1693, 2022

Authors: Castillo-Passi, Rolando I. | Vergara, Rodrigo C. | Rogers, Nicole K. | Ponce, Daniela P. | Bennett, Magdalena | Behrens, María Isabel

Article Type: Research Article

Abstract: Background: Several epidemiological studies report a negative association between Cancer and Alzheimer’s disease (AD). Objective: To characterize the trajectories of memory loss in individuals with early amnestic cognitive impairment with and without history of previous cancer. Methods: Cognitive deterioration was assessed using the Montreal Cognitive Assessment (MoCA) or MoCA-Memory Index Score (MoCA-MIS) biannually in subjects with early amnestic cognitive impairment followed-up retrospectively from 2007 to 2021. History of Cancer was obtained from clinical records. Simple linear regressions of MoCA-MIS scores were calculated for each subject and analyzed with K-means cluster analysis to identify subgroups with different …cognitive decline trajectories. χ2 and t tests were used for descriptive categorical and continuous variables and mixed multiple linear regressions to determine cognitive decline covariates. Results: Analysis of the trajectory of cognitive decline in 141 subjects with early amnestic cognitive impairment identified two subgroups: Fast (n  = 60) and Slow (n  = 81) progressors. At baseline Fast progressors had better MoCA-MIS (p  < 0.001) and functionality (CDR p  = 0.02, AD8 p  = 0.05), took less anti-dementia medications (p  = 0.005), and had higher depression rates (p  = 0.02). Interestingly, Fast progressors slowed their speed of memory decline (from 1.6 to 1.1 MoCA-MIS points/year) and global cognitive decline (from 2.0 to 1.4 total MoCA points/year) when Cancer history was present. Conclusion: Two trajectories of amnestic cognitive decline were identified, possibly derived from different neurophysiopathologies or clinical stages. This study suggests that a history of previous Cancer slows down amnestic cognitive decline, specifically in a subgroup of subjects with depression at baseline and accelerated deterioration at follow-up. Show more

Keywords: Alzheimer’s disease, cognitive decline, cancer history, memory, mild cognitive impairment

DOI: 10.3233/JAD-215660

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1695-1711, 2022

Authors: Sun, Mengzi | Wang, Ling | Guo, Yinpei | Yan, Shoumeng | Li, Jing | Wang, Xuhan | Li, Xiaotong | Li, Bo

Article Type: Research Article

Abstract: Background: Dietary inflammatory index (DII) was associated with Type 2 diabetes mellitus and cognitive function impairment (CFI). Objective: The aim of this study was to explore whether the associations among DII, glycohemoglobin (HbA1c), and CFI were similar in the participants with or without diabetes. Methods: A total of 1,198 participants aged 60 and over from the National Health and Nutrition Examination Survey (NHANES) in 2011–2014 were involved in this study, dividing into subgroups as diabetes and non-diabetes for further analysis. Results: We found that participants with pro-inflammatory diet had higher proportion of CFI patients …(p  < 0.05). Pro-inflammatory diet and HbA1c were positively associated with the risk of CFI; participants with pro-inflammatory diet was 1.479 times on occurrence of CFI compared with anti-inflammatory diet group. The interaction between inflammatory diet and HbA1c was positive on the risk of CFI and was negative on the CERAD-immediate and CERAD-delayed, respectively. Among the participants without diabetes, the associations of Energy-adjusted DII (E-DII) with Animal Fluency test and Digit Symbol Substitution Test (DSST) were partially mediated by HbA1c, and the mediated proportion was 5.8% and 6.6%, respectively. However, there was no such mediation effect in the diabetes patients. Conclusion: In elderly participants without diabetes, there was an interaction between inflammatory diet and HbA1c on the association with CFI, especially for the dimension of CERAD-immediate and CERAD-delayed. Besides, the associations of E-DII with Animal Fluency test and DSST were partially mediated by HbA1c. For diabetic patients, HbA1c, rather than the inflammatory diet has a positive effect on the CFI risk. Show more

Keywords: Cognitive function, diabetes, energy-adjusted dietary inflammatory index, HbA1c, inflammatory diet

DOI: 10.3233/JAD-215688

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1713-1723, 2022

Authors: Wuttke-Linnemann, Alexandra | Henrici, Clara | Skoluda, Nadine | Nater, Urs M. | Endres, Kristina | Fellgiebel, Andreas

Article Type: Research Article

Abstract: Background: Research concerning people living with dementia (PwD) and their informal caregivers (ICs) has recently begun to focus on dyadic aspects of psychosocial interventions. Objective: We adapted a dyadic psychosocial intervention and examined its effects on psychobiological stress in daily life. Methods: Twenty-four PwD-caregiver dyads were visited seven times at home by specialized nursing staff. Momentary subjective stress, salivary cortisol (sCort), and salivary alpha-amylase (sAA) were measured in PwD and ICs before and after each home visit as well as six times per day at two days each at the beginning and end of the intervention …as part of an ambulatory assessment. Hair cortisol concentrations (HCC) were measured twice. Results: After each home visit session, ICs reported lower subjective stress. sCort was lower in both ICs and PwD, whereas sAA did not change. In daily life, area under the curve (AUCg) concerning sCort secretion indicated that PwD had lower sCort daily output at the end of the intervention, and AUCg concerning subjective stress indicated that both PwD and ICs reported lower subjective stress than at the beginning of the intervention. AUCg concerning sAA did not change over time in either group. HCC did not vary over time but increased with disease severity. Conclusion: The psychosocial intervention reduced psychobiological stress but affected psychobiological stress measures differently in PwD and ICs. In particular, the discrepancy between subjective and physiological markers of stress in PwD emphasizes the added value to evaluate treatment success and understand underlying mechanisms as a complement to self-reports. Show more

Keywords: Cognitive-behavioral therapy, coping, dementia care, home-based, resilience

DOI: 10.3233/JAD-210618

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1725-1739, 2022