Journal of Alzheimer's Disease - Volume 91, issue 1

Authors: Tan, Wei Ying | Hargreaves, Carol | Chen, Christopher | Hilal, Saima

Article Type: Research Article

Abstract: Background: The major mechanisms of dementia and cognitive impairment are vascular and neurodegenerative processes. Early diagnosis of cognitive impairment can facilitate timely interventions to mitigate progression. Objective: This study aims to develop a reliable machine learning (ML) model using socio-demographics, vascular risk factors, and structural neuroimaging markers for early diagnosis of cognitive impairment in a multi-ethnic Asian population. Methods: The study consisted of 911 participants from the Epidemiology of Dementia in Singapore study (aged 60– 88 years, 49.6% male). Three ML classifiers, logistic regression, support vector machine, and gradient boosting machine, were developed. Prediction results of …independent classifiers were combined in a final ensemble model. Model performances were evaluated on test data using F1 score and area under the receiver operating curve (AUC) methods. Post modelling, SHapely Additive exPlanation (SHAP) was applied on the prediction results to identify the predictors that contribute most to the cognitive impairment prediction. Findings: The final ensemble model achieved a F1 score and AUC of 0.87 and 0.80 respectively. Accuracy (0.83), sensitivity (0.86), specificity (0.74) and predictive values (positive 0.88 negative 0.72) of the ensemble model were higher compared to the independent classifiers. Age, ethnicity, highest education attainment and neuroimaging markers were identified as important predictors of cognitive impairment. Conclusion: This study demonstrates the feasibility of using ML tools to integrate multiple domains of data for reliable diagnosis of early cognitive impairment. The ML model uses easy-to-obtain variables and is scalable for screening individuals with a high risk of developing dementia in a population-based setting. Show more

Keywords: Cognitive impairment, machine learning, socio-demographic, structural MRI, vascular risk factors

DOI: 10.3233/JAD-220776

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 449-461, 2023

Authors: Li, Jian-Guo | Blass, Benjamin E. | Praticò, Domenico

Article Type: Research Article

Abstract: Background: The endosomal retromer complex system is a key controller for trafficking of proteins. Downregulation of its recognition core proteins, such as VPS35, is present in Alzheimer’s disease (AD) brain, whereas its normalization prevents the development of AD pathology in a transgenic model with amyloid-β deposits and tau tangles. Objective: Assess the effect of targeting VPS35 after the AD pathology and memory impairments have developed. Methods: Twelve-month-old triple transgenic mice were treated with a small pharmacological chaperone, TPT-172, or vehicle for 14 weeks. At the end of this period, the effect of the drug on their …phenotype was evaluated. Results: While control mice had a decline of learning and memory, the group receiving the chaperone did not. Moreover, when compared with controls the treated mice had significantly less amyloid-β peptides and phosphorylated tau, elevation of post-synaptic protein, and reduction in astrocytes activation. Conclusion: Taken together, our findings demonstrate that pharmacologic stabilization of the retromer recognition core is beneficial also after the AD-like pathologic phenotype is established. Show more

Keywords: Alzheimer’s disease, amyloid-β, pharmacological chaperone, retromer complex, tau protein

DOI: 10.3233/JAD-220869

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 463-469, 2023

Authors: Quintana-Hernández, Domingo J. | Rojas-Hernández, Jaime | Santana-del Pino, Angelo | Céspedes Suárez, Carmen | Pellejero Silva, Mónica | Miró-Barrachina, María Teresa | Ibáñez Fernández, Ignacio | Estupiñán López, José Antonio | Borkel, Lucas F.

Article Type: Research Article

Abstract: Background: This longitudinal study addressed whether mindfulness practice prevents psychological and behavioral symptoms, especially mood disorders, in Alzheimer’s disease (AD). Objective: To assess the incidence of depression in the course of AD and to determine which non-pharmacological treatment (NPT) is most effective in preventing psychopathological symptoms. Methods: We conducted a longitudinal, non-inferiority and equivalence randomized clinical trial, repeated-measures design, with a control group and three experimental treatments: mindfulness, cognitive stimulation, and relaxation. Each experimental group performed three weekly sessions for two years. The pharmacological treatment of all participants was donepezil (10 mg). Participants were patients with probable …AD without diagnosed depression from the public neurology services of the Canary Health Service, Spain. Psychological evaluation was performed using the Geriatric Depression Scale (GDS), Hamilton Depression Rating Scale (HDRS), and Neuropsychiatric Inventory (NPI-Q). The statistical analysis included only patients who attended at least 75% of the sessions. A nonparametric, repeated-measures analysis was performed with Kruskal-Wallis H test and between-group differences with Mann-Whitney U test with Bonferroni correction (p  < 0.008). Effect size was calculated with partial eta-squared. Results: The results showed significant differences with large effect sizes (η2 p >0.14) between mindfulness and the rest of the experimental groups as well as the control in the GDS, HDRS, and NPI-Q scales. Conclusion: Compared to the other experimental groups, only mindfulness prevented the onset of depression and other psychopathologies in early-stage AD. Based on its effectiveness in maintaining cognitive functions and preventing psychopathology, we recommend mindfulness as the first-choice NPT for mild to moderate AD. Show more

Keywords: Alzheimer’s disease, cognitive stimulation, mindfulness, randomized clinical trial, relaxation

DOI: 10.3233/JAD-220889

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 471-481, 2023

Authors: Petrella, Jeffrey R. | Michael, Andrew M. | Qian, Min | Nwosu, Adaora | Sneed, Joel | Goldberg, Terry E. | Devanand, Davangere P. | Doraiswamy, P. Murali

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) represents a high risk group for Alzheimer’s disease (AD). Computerized Cognitive Games Training (CCT) is an investigational strategy to improve targeted functions in MCI through the modulation of cognitive networks. Objective: The goal of this study was to examine the effect of CCT versus a non-targeted active brain exercise on functional cognitive networks. Methods: 107 patients with MCI were randomized to CCT or web-based crossword puzzles. Resting-state functional MRI (fMRI) was obtained at baseline and 18 months to evaluate differences in fMRI measured within- and between-network functional connectivity (FC) of the …default mode network (DMN) and other large-scale brain networks: the executive control, salience, and sensorimotor networks. Results: There were no differences between crosswords and games in the primary outcome, within-network DMN FC across all subjects. However, secondary analyses suggest differential effects on between-network connectivity involving the DMN and SLN, and within-network connectivity of the DMN in subjects with late MCI. Paradoxically, in both cases, there was a decrease in FC for games and an increase for the crosswords control (p  < 0.05), accompanied by lesser cognitive decline in the crosswords group. Conclusion: Results do not support a differential impact on within-network DMN FC between games and crossword puzzle interventions. However, crossword puzzles might result in cognitively beneficial remodeling between the DMN and other networks in more severely impaired MCI subjects, parallel to the observed clinical benefits. Show more

Keywords: Alzheimer’s disease, biomarkers, default mode network, digital therapeutics, functional MRI, mild cognitive impairment, neuroplasticity

DOI: 10.3233/JAD-220946

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 483-494, 2023

Authors: Daniel, E. Valerie | Kleiman, Michael J. | Galvin, James E.

Article Type: Research Article

Abstract: Background: African American and Hispanic older adults are reported to have up to a 2-fold higher risk of Alzheimer’s disease and related disorders (ADRD), but the reasons for this increased vulnerability have not been fully explored. The Vulnerability Index (VI) was designed to identify individuals who are at risk of developing cognitive impairment in the future, capturing 12 sociodemographic variables and modifiable medical comorbidities associated with higher ADRD risk. However, a prior limitation of the VI was that the original study cohort had limited diversity. We examined the association of the VI within and between non-Hispanic White, African American, and …Hispanic older adults with and without cognitive impairment and different socioeconomic strata enrolled in a community-based dementia screening study. Objective: To explore reasons for reported higher ADRD vulnerability in African Americans and Hispanics. Methods: In a cross-sectional study of 300 non-Hispanic White, African American, and Hispanic older adults with and without cognitive impairment, we studied the association between cognitive status, the VI, and socioeconomic status (SES). Results: When considering race/ethnicity, the presence of more vascular comorbidities drove greater vulnerability. When considering SES, vascular comorbidities played a less prominent role suggesting resources and access to care drives risk. The VI had differential effects on cognitive performance with the greatest effect in the earlier stages of impairment. Conclusion: Findings from this study provide a deeper understanding of the differential risk of ADRD in multicultural older adults captured by the VI and how barriers to healthcare access may increase vulnerability in racial/ethnic minorities. Show more

Keywords: Alzheimer’s disease, cognitive impairment, dementia, health disparities, mild cognitive impairment, race/ethnicity, risk assessment, risk factors, socioeconomic status, vulnerability

DOI: 10.3233/JAD-220959

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 495-506, 2023