Journal of Alzheimer's Disease - Volume 96, issue 2

Authors: Bahrani, Ahmed A. | Abner, Erin L. | DeCarli, Charles S. | Barber, Justin M. | Sutton, Abigail C. | Maillard, Pauline | Sandoval, Francisco | Arfanakis, Konstantinos | Yang, Yung-Chuan | Evia, Arnold M. | Schneider, Julie A. | Habes, Mohamad | Franklin, Crystal G. | Seshadri, Sudha | Satizabal, Claudia L. | Caprihan, Arvind | Thompson, Jeffrey F. | Rosenberg, Gary A. | Wang, Danny J.J. | Jann, Kay | Zhao, Chenyang | Lu, Hanzhang | Rosenberg, Paul B. | Albert, Marilyn S. | Ali, Doaa G. | Singh, Herpreet | Schwab, Kristin | Greenberg, Steven M. | Helmer, Karl G. | Powel, David K. | Gold, Brian T. | Goldstein, Larry B. | Wilcock, Donna M. | Jicha, Gregory A.

Article Type: Research Article

Abstract: Background: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer’s Disease. Objective: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol. Methods: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were …analyzed in relation to WMH changes to explore its construct validity. Results: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression. Conclusions: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression. Show more

Keywords: Aging, Alzheimer’s disease, cerebrovascular disease, dementia, longitudinal, MarkVCID, small vessel ischemic disease, white matter hyperintensity

DOI: 10.3233/JAD-230629

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 683-693, 2023

Authors: Kravatz, Nigel L. | Adhikari, Dristi | Ayers, Emmeline | Verghese, Joe

Article Type: Research Article

Abstract: Background: Motoric cognitive risk syndrome (MCR), a pre-dementia syndrome characterized by subjective cognitive complaints and slow gait, is associated with disability in instrumental activities of daily living. It is unknown whether these functional limitations occur even before this pre-dementia syndrome is diagnosed. Objective: To assess profiles of complex and instrumental activities of daily living in the prodromal stages of MCR. Methods: We examined functional profiles in 46 older adults (mean age 79 years, 59% women) living in the community with normal cognition at baseline who developed MCR over follow-up (‘pre-MCR’) with 264 older adults (mean age …75 years, 57% women) who remained cognitively intact over the follow-up period. Results: Pre-MCR individuals had more limitations on complex everyday function at baseline compared to normal controls in multivariable logistic regression models (odds ratio 1.21). Pre-MCR cases at baseline had limitations in handling finances (odds ratio 3.0) and performing hobbies (odds ratio 5.5) as compared to normal controls. Pre-MCR cases had a greater difference in the number of complex functional limitations from baseline to MCR compared to the difference from baseline to final visit for the controls (1.2±3.0 versus 0.5±2.2, p  < 0.001). Conclusions: Limitations in complex everyday tasks arise in the prodromal stages of MCR and can assist in risk prognostication. Show more

Keywords: Activities of daily living, Alzheimer’s disease, functional status, motoric cognitive risk syndrome

DOI: 10.3233/JAD-230579

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 695-704, 2023

Authors: Xue, Weiqi | He, Weifeng | Yan, Mengyuan | Zhao, Huanyi | Pi, Jianbin

Article Type: Research Article

Abstract: Background: Patients are at increased risk of dementia, including Alzheimer’s disease (AD), after myocardial infarction (MI), but the biological link between MI and AD is unclear. Objective: To understand the association between the pathogenesis of MI and AD and identify common biomarkers of both diseases. Methods: Using public databases, we identified common biomarkers of MI and AD. Least absolute shrinkage and selection operator (LASSO) regression and protein-protein interaction (PPI) network were performed to further screen hub biomarkers. Functional enrichment analyses were performed on the hub biomarkers. Single-cell/nucleus analysis was utilized to further analyze the hub biomarkers …at the cellular level in carotid atherosclerosis and AD datasets. Motif enrichment analysis was used to screen key transcription factors. Results: 26 common differentially expressed genes were screened between MI and AD. Function enrichment analyses showed that these differentially expressed genes were mainly associated with inflammatory pathways. A key gene, Regulator of G-protein Signaling 1 (RGS1), was obtained by LASSO regression and PPI network. RGS1 was confirmed to mainly express in macrophages and microglia according to single-cell/nucleus analysis. The difference in expression of RGS1 in macrophages and microglia between disease groups and controls was statistically significant (p  < 0.0001). The expression of RGS1 in the disease groups was upregulated with the differentiation of macrophages and microglia. RelA was a key transcription factor regulating RGS1. Conclusion: Macrophages and microglia are involved in the inflammatory response of MI and AD. RGS1 may be a key biomarker in this process. Show more

Keywords: Alzheimer’s disease, bioinformatics, myocardial infarction, single-cell RNA sequencing, single-nucleus RNA sequencing

DOI: 10.3233/JAD-230559

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 705-723, 2023

Authors: He, Qiang | Wang, Wenjing | Li, Hao | Xiong, Yang | Tao, Chuanyuan | Ma, Lu | You, Chao

Article Type: Research Article

Abstract: Background: The role of metabolic syndrome (MetS) on dementia is disputed. Objective: We conducted a Mendelian randomization to clarify whether the genetically predicted MetS and its components are casually associated with the risk of different dementia types. Methods: The genetic predictors of MetS and its five components (waist circumference, hypertension, fasting blood glucose, triglycerides, and high-density lipoprotein cholesterol [HDL-C]) come from comprehensive public genome-wide association studies (GWAS). Different dementia types are collected from the GWAS in the European population. Inverse variance weighting is utilized as the main method, complemented by several sensitivity approaches to verify the …robustness of the results. Results: Genetically predicted MetS and its five components are not causally associated with the increasing risk of dementia (all p  > 0.05). In addition, no significant association between MetS and its components and Alzheimer’s disease, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and dementia due to Parkinson’s disease (all p  > 0.05), except the association between HDL-C and dementia with Lewy bodies. HDL-C may play a protective role in dementia with Lewy bodies (OR: 0.81, 95% CI: 0.72–0.92, p  = 0.0010). Conclusions: From the perspective of genetic variants, our study provides novel evidence that MetS and its components are not associated with different dementia types. Show more

Keywords: Alzheimer’s disease, causal association, components, dementia, Mendelian randomization, metabolic syndrome, types

DOI: 10.3233/JAD-230623

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 725-743, 2023

Authors: Lee, Alina | Shan, Di | Castle, David | Rajji, Tarek K. | Ma, Clement

Article Type: Research Article

Abstract: Background: Drug development in Alzheimer’s disease (AD) over the past two decades has had high rates of failure. Novel trial designs, such as adaptive designs, have the potential to improve the efficiency of drug development in AD. Objective: To evaluate the design characteristics, temporal trends, and differences in design between sponsor types in phase II trials of investigational agents in AD. Methods: Phase I/II, II, and II/III trials for AD with drug or other biological interventions registered from December 1996 to December 2021 in ClinicalTrials.gov were included. Descriptive statistics were used to summarize trial characteristics. Linear, …logistic, and multinomial regression models assessed temporal trends and differences between sponsor types in design characteristics. Results: Of N  = 474 trials identified, randomized parallel group design was the most common design (72%). Only 12 trials (2.5%) used an adaptive design; adaptive features included early stopping rules, model-based dose-finding, adaptive treatment arm selection, and response adaptive randomization. The use of non-randomized parallel-group and open-label single arm designs increased over time. No temporal trend in the use of adaptive design was identified. Trials sponsored by industry only were more likely to use a randomized parallel-group design and have a larger estimated sample size than trials with other sponsor types. Conclusion: Our systematic review showed that very few phase II trials in AD used an adaptive trial design. Innovation and implementation of novel trial designs in AD trials can accelerate the drug development process. Show more

Keywords: Adaptive designs, Alzheimer’s disease, novel trial designs, phase II trials, systematic review

DOI: 10.3233/JAD-230660

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 745-757, 2023

Authors: Alkon, Daniel L. | Sun, Miao-Kun | Tuchman, Alan J. | Thompson, Richard E.

Article Type: Research Article

Abstract: Background: In pre-clinical studies, Bryostatin, MW (molecular weight) 904, has demonstrated synaptogenic, anti-apoptotic, anti-amyloid, and anti-tau tangle efficacies. Objective: To identify AD patients who show significant cognitive benefit versus placebo when treated in a trial with chronic Bryostatin dosing. Methods: In this 6-month 122 AD patient Bryostatin trial, there were two cohorts: the Moderate Cohort (MMSE, Mini-Mental Status Exam: 15-18) and the Moderately Severe Cohort (MMSE 10-14) as pre-specified secondary endpoints. Patient randomization was stratified by baseline SIB to insure balance in baseline cognitive ability between treatment arms. Results: With no safety events noted …by the data safety and monitoring board, the Moderately Severe (MMSE 10-14) Bryostatin-treated patients were significantly improved above the placebo patients for Weeks #13 through Week #42. After two cycles of 7 x i.v. Bryostatin doses over a 26-week period, the 10-14 Cohort Severe Impairment Battery (SIB), measured every 2 weeks, showed significant benefit using a Mixed Model Repeated Measures model (MMRM, 2-tailed, p  < 0.05) for Weeks #13 through #42, even 16 weeks after dosing completion by Week #26. Placebo 10-14 patients showed no benefit, declining to negative 12.8 points by Week #42. Trend analyses confirmed the MMRM data for this Cohort, with a significant downward slope (equivalent to Cognitive Decline) for the placebo group, p  < 0.001, 2-tailed, but no significant decline for the Bryostatin-treated group (p  = 0.409, NS), treatment versus placebo p  < 0.007. The Moderate Cohort patients showed no significant benefit. Conclusions: The Bryostatin-treated MMSE 10-14 patients showed no significant cognitive decline throughout the 10-month trial, versus placebo patients’ decline of -12.8 SIB points. Show more

Keywords: Alzheimer’s disease, Bryostatin, moderately severe AD patients, prevention, safety

DOI: 10.3233/JAD-230868

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 759-766, 2023

Authors: Ingannato, Assunta | Bessi, Valentina | Chiari, Annalisa | Salvatori, Davide | Bagnoli, Silvia | Bedin, Roberta | Ferrari, Camilla | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Research Article

Abstract: Background: Progranulin protein (GRN) is a growth factor, encoded by the GRN (Granulin precursor) gene, involved in several functions including inflammation, wound repair, signal transduction, proliferation, and tumorigenesis. Mutations in GRN gene are usually the genetic etiology of frontotemporal dementia (FTD), but different studies reported GRN mutations in Alzheimer ’s disease (AD) patients. Objective: Here, we analyzed FTD linked gene GRN in 23 patients with a clinical diagnosis of AD and a family history of AD (FAD), not carrying mutations in AD candidate genes (PSEN 1, PSEN 2 , and APP ). In addition, …Microtubule-associated protein tau (MAPT ) gene was studied too. All patients underwent an extensive neuropsychological battery. Methods: Genetic analyses were performed thought PCR assay and sequencing. Variants were annotated with ANNOVAR and allele frequency was checked on population databases. In silico prediction tools were consulted to check nonsynonymous variants and their effect on protein function and structure. The clinical data were retrospectively collected from medical records. Results: Genetic screening of MAPT and GRN in 23 FAD patients highlighted two rare different variants in two probands (2/23 = 8,7%) located in GRN gene: R433W (p.Arg433Trp) and C521Y (p.Cys521Tyr). The R433W and C521Y are variants with uncertain significant, that are predicted to affect GRN protein structure and function, with a possible damaging effect. Conclusions: Our data provide evidence of the importance of GRN genetic analysis also in the study of familial AD. Show more

Keywords: Alzheimer’s disease, genetic variants, GRN , Progranulin

DOI: 10.3233/JAD-230689

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 767-775, 2023

Authors: Larsson, Liss Elin | Wang, Rui | Cederholm, Tommy | Wiggenraad, Fleur | Rydén, Marie | Hagman, Göran | Hellénius, Mai-Lis | Kivipelto, Miia | Thunborg, Charlotta

Article Type: Research Article

Abstract: Background: Sarcopenia and cognitive impairment are two leading causes of disabilities. Objective: The objective was to examine the prevalence of sarcopenia and investigate the association between sarcopenia diagnostic components (muscle strength, muscle mass, and physical performance) and cognitive impairment in memory clinic patients. Methods: 368 patients were included (age 59.0±7.25 years, women: 58.7%), displaying three clinical phenotypes of cognitive impairments, i.e., subjective cognitive impairment (SCI, 57%), mild cognitive impairment (MCI, 26%), and Alzheimer’s disease (AD, 17%). Sarcopenia was defined according to diagnostic algorithm recommended by the European Working Group on Sarcopenia in Older People. Components …of sarcopenia were grip strength, bioelectrical impedance analysis, and gait speed. They were further aggregated into a score (0–3 points) by counting the numbers of limited components. Multi-nominal logistic regression was applied. Results: Probable sarcopenia (i.e., reduced grip strength) was observed in 9.6% of the patients, and 3.5% were diagnosed with sarcopenia. Patients with faster gait speed showed less likelihood of MCI (odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.06–0.90) and AD (OR: 0.12, 95% CI: 0.03–0.60). One or more limited sarcopenia components was associated with worse cognitive function. After adjusting for potential confounders, the association remained significant only for AD (OR 4.29, 95% CI 1.45–11.92). Conclusion: The results indicate a connection between the sarcopenia components and cognitive impairments. Limitations in the sarcopenia measures, especially slow walking speed, were related to poorer cognitive outcomes. More investigationsare required to further verify the causal relationship between sarcopenia and cognitive outcomes. Show more

Keywords: Alzheimer’s disease, body composition, cognitive function, gait speed, hand grip strength, outpatients, sarcopenia

DOI: 10.3233/JAD-221186

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 777-788, 2023

Authors: Hoang, Minh Tuan | Kåreholt, Ingemar | Schön, Pär | von Koch, Lena | Xu, Hong | Tan, Edwin C.K | Johnell, Kristina | Eriksdotter, Maria | Garcia-Ptacek, Sara

Article Type: Research Article

Abstract: Background: Long-term care improves independence and quality of life of persons with dementia (PWD). The influence of socioeconomic status on access to long-term care was understudied. Objective: To explore the socioeconomic disparity in long-term care for PWD. Methods: This registry-based study included 14,786 PWD, registered in the Swedish registry for cognitive and dementia disorders (2014–2016). Education and income, two traditional socioeconomic indicators, were the main exposure. Outcomes were any kind of long-term care, specific types of long-term care (home care, institutional care), and the monthly average hours of home care. The association between outcomes and socioeconomic …status was examined with zero-inflated negative binomial regression and binary logistic regression. Results: PWD with compulsory education had lower likelihood of receiving any kind of long-term care (OR 0.80, 95% CI 0.68–0.93), or home care (OR 0.83, 95% CI 0.70–0.97), compared to individuals with university degrees. Their monthly average hours of home care were 0.70 times (95% CI 0.59–0.82) lower than those of persons with university degrees. There was no significant association between education and the receipt of institutional care. Stratifying on persons with Alzheimer’s disease showed significant association between lower education and any kind of long-term care, and between income and the hours of home care. Conclusions: Socioeconomic inequalities in long-term care existed in this study population. Lower-educated PWD were less likely to acquire general long-term care, home care and had lower hours of home care, compared to their higher-educated counterparts. Income was not significantly associated with the receipt of long-term care. Show more

Keywords: KeywordsAlzheimer’s disease, aged care, dementia, disparity, education, home care, income, inequality, institutional care, long-term care

DOI: 10.3233/JAD-230388

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 789-800, 2023

Authors: Li, Jing | Weiss, Jordan | Rajadhyaksha, Ashish | Acosta, Daisy | Harrati, Amal | Jiménez Velázquez, Ivonne Z. | Liu, Mao-Mei | Guerra, Jorge J. Llibre | Rodriguez, Juan de Jesús Llibre | Dow, William H.

Article Type: Research Article

Abstract: Background: Despite the high burden of Alzheimer’s disease and other dementias among the Hispanic population worldwide, little is known about how dementia affects healthcare utilizations among this population outside of the US, in particular among those in the Caribbean region. Objective: This study examines healthcare utilization associated with Alzheimer’s disease and other dementias among older adults in the Caribbean as compared to the US. Methods: We conducted harmonized analyses of two population-based surveys, the 10/66 Dementia Group Research data collected in Dominican Republic, Cuba, and Puerto Rico, and the US-based Health and Retirement Study. We examined …changes in hospital nights and physician visits in response to incident and ongoing dementias. Results: Incident dementia significantly increased the risk of hospitalization and number of hospital nights in both populations. Ongoing dementia increased the risk of hospitalization and hospital nights in the US, with imprecise estimates for the Caribbean. The number of physician visits was elevated in the US but not in the Caribbean. Conclusions: The concentration of increased healthcare utilization on hospital care and among patients with incident dementia suggests an opportunity for improved outpatient management of new and existing dementia patients in the Caribbean. Show more

Keywords: Alzheimer’s disease, Caribbean, dementia, healthcare utilization, Hispanics

DOI: 10.3233/JAD-230505

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 801-811, 2023