Journal of Alzheimer's Disease - Volume 90, issue 1

Authors: Cejudo, Juan Carlos | Samaniego, Melissa | Almeria, Marta | Castrillo, Susana | Medina, Lidia | Gil, Domènec

Article Type: Research Article

Abstract: Background: Semantic memory (SM) constitutes a cognitive system that is seriously affected by Alzheimer’s disease (AD). There are several tests for assessing SM, but a tool is needed to assess AD in the early stages of the illness. Objective: The study aimed to create, validate, and normalize a new test to assess SM, called the Ikos test, for AD and early AD in clinical practice. Methods: 62 healthy adults as a control group (CG), 62 AD, and 60 amnestic mild cognitive impairment (aMCI) subdivided into a group that progresses to AD, and another group that does …not progress to AD were selected. The internal consistency (IC), the construct validity (CV), and reliability between raters and the test-retest were analyzed. We used the Bayesian approach to establish the accuracy of the diagnosis of the Ikos test in AD and early AD. Results: IC showed a Kuder-Richardson index of r = 0.945. The CV between the Ikos test and Pyramids and Palm Trees; Intraclass Correlation Coefficient (ICC) index was 0.897. The Kappa index was between 0.865 and 0.912, and the ICC index was 0.873 for the test-retest reliability. The Area Under the Curve was 0.981, sensitivity (SE) was 0.95, and specificity (SP) was 0.96 in AD/CG. In contrast, in the MCI-AD/CG group, SE = 0.77 and SP = 0.80. Conclusion: The Ikos test accomplishes the criteria of validity and reliability with high correlation indexes. Therefore, it can be considered a valid, reliable, and easily applicable tool for SM assessment in diagnosing AD and the early stages of clinical disease. Show more

Keywords: Early Alzheimer’s disease, neuropsychology of memory, semantic knowledge, semantic knowledge in dementia, semantic memory test

DOI: 10.3233/JAD-220516

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 151-160, 2022

Authors: Tariot, Pierre N. | Braeckman, Rene | Oh, Charles

Article Type: Research Article

Abstract: Background: Donepezil is approved for treatment of dementia of the Alzheimer type and is currently available only in tablet forms in the United States. Objective: To compare steady-state pharmacokinetics of once-weekly 10-mg/d and 5-mg/d Corplex™ donepezil transdermal delivery systems (TDS) with once-daily 10-mg oral donepezil. Methods: Open-label, randomized, crossover study (NCT04617782) enrolled healthy participants aged 18–55 years. All participants received 5-mg/d donepezil TDS during the 5-week Period 1, followed by 10-mg/d TDS or 10-mg/d oral donepezil in the 5-week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state on Week 5. …Results: All 60 enrolled participants received 5-mg/d TDS, 55 received 10-mg/d TDS, and 56 received oral donepezil. Adjusted geometric mean ratio (% [90% CI]) for maximum plasma concentration and area under the plasma concentration versus time curve (0–168 h) were 88.7 (81.7–96.2) and 108.6 (100.5–117.4) for 10-mg/d and 86.1 (79.8–92.9) and 105.3 (97.6–113.6) for dose-normalized 5-mg/d TDS and were generally within the 80% –125% range for establishing bioequivalence with oral donepezil. Skin adhesion was similar for both TDSs (>80% of patches remaining ≥75% adhered throughout the wear period). Overall incidence of adverse events (AEs) was similar across treatments. Compared with 10-mg/d TDS, oral donepezil was associated with higher incidence of gastrointestinal and nervous system AEs (14.5% versus 53.6% and 14.5% versus 30.4%, respectively). Conclusion: Donepezil TDSs are bioequivalent to oral donepezil at steady state and have a safety profile that supports their use in treating dementia of the Alzheimer type. Show more

Keywords: Alzheimer’s disease, Alzheimer type dementia, bioequivalence, donepezil, transdermal patch

DOI: 10.3233/JAD-220530

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 161-172, 2022

Authors: Zhang, Jinhuan | Hu, Shan | Liu, Yongfeng | Lyu, Hanqing | Huang, Xingxian | Li, Xinbei | Chen, Jianxiang | Hu, Qingmao | Xu, Jinping | Yu, Haibo

Article Type: Research Article

Abstract: Background: Although acupuncture is widely used to improve cognitive and memory in the amnesic mild cognitive impairment (aMCI) patients with impressive effectiveness, its neural mechanism remains largely unclear. Objective: We aimed to explore functional magnetic resonance imaging (fMRI) mechanism of acupuncture for aMCI. Methods: A randomized, controlled, single-blind research was performed. A total of 46 aMCI patients were randomly assigned into verum and sham acupuncture group, who received a total of 24 times treatments (3 times/week, 8 weeks). Clinical evaluation and fMRI scanning were performed at baseline and after treatment for all aMCI patients. The interaction …effects and inter-group effects of regional homogeneity (ReHo) were performed using mixed effect models, and the correlations between clinical improvement and neuroimaging changes before and after verum acupuncture treatment were analyzed using Pearson correlations. Results: As a result, interaction effects showed increased ReHo value in left dorsal lateral prefrontal cortex (DLPFC), increased functional connectivity between left DLPFC and left precuneus, and decreased functional connectivity between left DLPFC and left inferior temporal gyrus after verum acupuncture but inversely after sham acupuncture in the aMCI. Condition effects showed increased ReHo in right lingual gyrus, and bilateral post-central gyrus after verum and sham acupuncture in the aMCI. In addition, the changed Montreal Cognitive Assessment scores in verum acupuncture group were significantly correlated with changed ReHo values in left DLPFC. Conclusion: Together, our findings further confirmed that acupuncture could be used as a promising complementary therapy for aMCI by modulating function of left DLPFC to improve cognitive symptoms. Show more

Keywords: Acupuncture, amnesic mild cognitive impairments, dorsal lateral prefrontal cortex, regional homogeneity

DOI: 10.3233/JAD-220592

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 173-184, 2022

Authors: Peng, Yan | Zhang, Li | Zhou, Fanlin | Wang, Yangyang | Zhang, Xiong | Fan, Jianing | Li, Shijie | Li, Xiaoju | Li, Yu

Article Type: Research Article

Abstract: Background: Dysregulated glucose metabolism in the brain is considered to be one of the key causes of Alzheimer’s disease (AD). Abnormal glucose uptake in AD is tightly associated with decreased levels of glucose transporter 1 (GLUT1) and GLUT3 in the brain, but the underlying mechanisms remain unclear. Objective: We aimed to explore the cause and mechanism of impaired glucose uptake in AD. Methods: N2a/WT and N2a/APP695swe cells were cultured in vitro , and cellular glucose uptake and ATP content, as well as the expression of GLUT1, GLUT3, and PI3K/Akt pathway members, were detected. Intracellular reactive oxygen …species (ROS) levels were detected by flow cytometry. After treatment with the ROS scavenger N-acetyl-L-cysteine (NAC), the above indicators were detected again. Results: GLUT1 expression was significantly decreased (p  = 0.0138) in N2a/APP695swe cells, while GLUT3 expression was no statistical difference (p  > 0.05). After NAC treatment, PI3K and Akt phosphorylation levels, GLUT1 expression, glucose uptake and ATP levels were remarkably increased (p  = 0.0006, p  = 0.0008, p  = 0.0009, p  = 0.0001, p  = 0.0013), while Aβ levels were significantly decreased (p  = 0.0058, p  = 0.0066). After addition of the PI3K inhibitor LY29004, GLUT1 expression was reduced (p  = 0.0008), and Aβ levels were increased (p  = 0.0009, p  = 0.0117). In addition, increases in glucose uptake and ATP levels induced by the Akt activator SC79 were hindered by the GLUT1 inhibitor WZB117 (p  = 0.0002, p  = 0.0005). Aβ levels were decreased after SC79 treatment and increased after WZB117 treatment (p  = 0.0212, p  = 0.0006). Conclusion: Taken together, scavenging of ROS prevents from Aβ deposition via activation of the PI3K/Akt/GLUT1 pathway, and improved the impaired glucose uptake in N2a/APP695swe cells. Show more

Keywords: Alzheimer’s disease, glucose uptake, GLUT1, PI3K/Akt, reactive oxygen species

DOI: 10.3233/JAD-220610

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 185-198, 2022

Authors: Silberstein, Richard B. | Pipingas, Andrew | Scholey, Andrew B.

Article Type: Research Article

Abstract: Background: Homocysteine, a methionine metabolite, is a recognized risk factor for accelerated age-related cognitive decline and dementia. Objective: In the light of studies indicating increases in brain activity and brain functional connectivity in the early stages of age-related cognitive decline, we undertook a study to examine the relationship between plasma homocysteine levels and brain functional connectivity in a group of late middle-aged males at risk of cognitive decline due to high body mass index and a sedentary lifestyle. Methods: Brain functional connectivity was measured using the steady state visual evoked potential event related partial coherence while …38 participants performed a memory task where each trial comprised an object recognition task followed by a location memory task. Results: We observed a significant transient peak in the correlation between plasma homocysteine levels and fronto-parietal brain functional connectivity immediately before the presentation of the memory location component of the task. Significantly, this correlation was only apparent if the participant pool included individuals with homocysteine concentrations above 11μmole/L. Conclusion: Our findings suggest that the increased brain functional connectivity observed in the earlier stages of age-related cognitive decline reflects pathognomonic changes in brain function and not compensatory changes engaged to enhance task performance. Our findings also suggest that homocysteine interferes with the inhibition of cortical networks where this inhibition is necessary for optimum task performance. Finally, we observed that the effect of homocysteine on brain functional connectivity is only apparent at concentrations above 11μmol/L. Show more

Keywords: Brain functional connectivity, cognitive decline, homocysteine, memory

DOI: 10.3233/JAD-220612

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 199-209, 2022

Authors: Du, Xianglin L. | Song, Lulu | Schulz, Paul E. | Xu, Hua | Chan, Wenyaw

Article Type: Research Article

Abstract: Background: Long term risk of Alzheimer’s disease (AD) and related dementias (ADRD) associated with vascular diseases in people with colorectal cancer is unknown. Objective: To determine the risk of ADRD in association with cardiovascular diseases (CVD), stroke, hypertension, and diabetes in a cohort of patients with colorectal cancer. Methods: This retrospective cohort study consisted of 210,809 patients diagnosed with colorectal cancer at age≥65 years in 1991–2015 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database with follow-up from 1991–2016, who were free of any ADRD at the baseline (<12 months prior to or < 30 days after …the date of cancer diagnosis). Results: The crude 26-year cumulative incidence of total ADRD in men and women with colorectal cancer was higher in those with versus without CVD (31.92% versus 28.12%), with versus without stroke (39.82% versus 26.39%), with versus without hypertension (31.88% versus 24.88%), and with versus without diabetes (32.01% versus 27.66%). After adjusting for socio-demographic and tumor factors, the risk of developing ADRD was significantly higher in patients with CVD (adjusted hazard ratio: 1.17, 95% confidence intervals: 1.14–1.20), stroke (1.65, 1.62–1.68), hypertension (1.07, 1.05–1.09), and diabetes (1.26, 1.24–1.29) versus persons without. For those with 1, 2, 3 and 4 vascular diseases present versus absent, the risk of AD increased from 1.12 (1.07–1.16) to 1.31 (1.25–1.36), 1.66 (1.57–1.75), and 2.03 (1.82–2.27). Conclusion: In older patients with colorectal cancer, a significant dose-response relationship was observed between an increasing number of these vascular diseases and the risk of all types of dementia. Show more

Keywords: Alzheimer’s disease, colorectal cancer, dementias, medicare, vascular diseases

DOI: 10.3233/JAD-220548

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 211-231, 2022

Authors: Nolan, John M. | Power, Rebecca | Howard, Alan N. | Bergin, Paula | Roche, Warren | Prado-Cabrero, Alfonso | Pope, George | Cooke, John | Power, Tommy | Mulcahy, Ríona

Article Type: Research Article

Abstract: Background: Preliminary work by our center has reported behavior and functional benefits in patients with Alzheimer’s disease (AD) following targeted micronutritional supplementation. Objective: To build on the existing exploratory research and investigate the impact of these micronutrients on the natural progression of AD in a randomized controlled trial. Methods: Patients with mild-moderate AD consumed daily 1 g fish oil (of which 500 mg DHA, 150 mg EPA), 22 mg carotenoids (10 mg lutein, 10 mg meso -zeaxanthin, 2 mg zeaxanthin), and 15 mg vitamin E or placebo for 12 months in a double-blind, placebo-controlled, randomized clinical trial. Carotenoids, ω-3FAs, and vitamin E were quantified …in blood. Carotenoids were also measured in skin. AD severity was measured using the mini-mental state examination and dementia severity rating scale tools. Behavior, mood, and memory were measured using an informant-based questionnaire. Results: Following 12 months of supplementation, the active group (n  = 50) compared to the placebo group (n  = 27), demonstrated statistically significant improvements in skin carotenoid measurements, blood carotenoids, ω-3FAs, and vitamin E concentrations (p  < 0.05, for all). The active group also performed better in objective measures of AD severity (i.e., memory and mood), with a statistically significant difference reported in the clinical collateral for memory (p  < 0.001). Conclusion: Exponential increases in the prevalence of AD and its relentless progressive nature is driving the need for interventions that help to ameliorate symptoms and improve quality of life in AD patients. Given the positive outcomes demonstrated in this trial, this combined micronutrient dietary supplement should be considered in the overall management of AD. Show more

Keywords: Alzheimer’s disease, antioxidants, carotenoids, clinical collateral, disease management, disease progression, nutrition, omega-3 fatty acids, vitamin E

DOI: 10.3233/JAD-220556

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 233-249, 2022

Authors: Migliorati, Martine | Manrique, Christine | Rahrah, Melinda | Escoffier, Guy | El Ahmadi, Abdessadek | Girard, Stéphane D. | Khrestchatisky, Michel | Rivera, Santiago | Baranger, Kévin | Roman, François S.

Article Type: Research Article

Abstract: Background: The 5XFAD model of Alzheimer’s disease (AD) bearing five familial mutations of Alzheimer’s disease on human APP and PSEN1 transgenes shows deposits of amyloid-β peptide (Aβ) as early as 2 months, while deficits in long-term memory can be detected at 4 months using the highly sensitive olfactory-dependent tests that we previously reported. Objective: Given that detecting early dysfunctions in AD prior to overt pathology is of major interest in the field, we sought to detect memory deficits at earlier stages of the disease in 3-month-old male 5XFAD mice. Methods: To this end, we …used the Helico Maze, a behavioral task that was recently developed and patented. This device allows deeper analysis of learning and subcategories of hippocampal-dependent long-term memory using olfactory cues. Results: Eight male 5XFAD and 6 male wild-type (WT: C57Bl6 background) mice of 3 months of age were tested in the Helico Maze. The results demonstrated, for the first time, a starting deficit of pure reference long-term memory. Interestingly, memory impairment was clearly correlated with Aβ deposits in the hippocampus. While we also found significant differences in astrogliosis between 5XFAD and WT mice, this was not correlated with memory abilities. Conclusion: Our results underline the efficiency of this new olfactory-dependent behavioral task, which is easy to use, with a small cohort of mice. Using the Helico Maze may open new avenues to validate the efficacy of treatments that target early events related to the amyloid-dependent pathway of the disease and AD progression. Show more

Keywords: Alzheimer’s disease, astrogliosis, 5XFAD mouse, Helico Maze, hippocampal Aβ deposits, reference memory deficit

DOI: 10.3233/JAD-220281

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 251-262, 2022

Authors: Wang, Ge | Estrella, Alliyah | Hakim, Ornin | Milazzo, Paul | Patel, Sonali | Pintagro, Clara | Li, Daniel | Zhao, Rui | Vance, David E. | Li, Wei

Article Type: Research Article

Abstract: Background: Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) are two commonly used cognitive screening and diagnostic tools. Objective: Our goal was to assess their efficacy for monitoring cognitive changes, as well as the correlation between the two tests. Methods: At baseline, participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were divided into four groups based on their cognitive diagnoses: healthy control (HC), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and Alzheimer’s disease (AD). MMSE or MoCA scores were compared among the four groups using an analysis of variance (ANOVA) model with …repeated measures with post-hoc Bonferroni correction. For those participants who had both MMSE and MoCA assessments done, a Pearson correlation analysis was performed between the two assessments for each visit. Results: The MMSE scores were significantly different among the four groups at baseline, which was true for each of the three annual follow-up visits. By contrast, the MoCA scores were not significantly different between HC and EMCI groups at either baseline or any of the follow-up visits. For participants with a diagnosis of LMCI, the cognitive performance deteriorated in a linear manner 12 months after the baseline, which was independent of MMSE or MoCA. At last, the MMSE scores were moderately related to MoCA scores, which got stronger along with the time of follow-up. Conclusion: MMSE and MoCA are comparable as cognitive assessment tools to monitor cognitive changes. In addition, the measurements of MMSE and MoCA are moderately correlated for the follow-up visits. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease neuroimaging initiative, apolipoprotein E, early mild cognitive impairment, healthy control, late mild cognitive impairment, mild cognitive impairment, Mini-Mental State Examination, Montreal Cognitive Assessment

DOI: 10.3233/JAD-220397

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 263-270, 2022

Authors: Sukik, Layan | Liu, Jianghong | Shi, Zumin

Article Type: Research Article

Abstract: Background: Previous studies suggest a positive effect of tea intake on cognition. Additional micronutrients that may moderate this association was not previously examined. Objective: To examine the association between tea consumption and cognition and explore the interaction between tea consumption and iron intake. Methods: Data from the China Health and Nutrition Survey between 1997 and 2011 was used. 4,820 individuals (≥55 years) were included in the analyses. Measurement of cognitive function was conducted in 1997, 2000, 2004, and 2006. Tea consumption was self-reported. Food intake was assessed by 24-hour dietary recalls of three consecutive days during …home visits between 1997 and 2011. Multivariable mixed linear regression and logistic regression was used to assess the association. Results: Tea consumption was associated with reduced global cognitive function decline. In fully adjusted models, regression coefficients (95% CIs) for those who consumed 0 cups/day,<2 cups/day, 2–3.9 cups/day, and≥4 cups/day of tea were 0, –0.09 (–0.55–0.37), 0.05 (–0.34–0.45), and 0.87 (0.46–1.29), respectively. This effect was stronger in adults > 60 years. Tea consumption of≥4 cups/day was inversely associated with self-reported poor memory (OR 0.70 (95% CI 0.56–0.86)) and memory decline (OR, 0.73 (95% CI 0.62–0.87)). There was a significant interaction between tea consumption and iron intake in relation to cognition. High iron intake was inversely associated with cognition in non-consumers of tea but not in tea consumers. Conclusion: Higher tea intake is associated with reduced cognitive decline in adults and inhibits the adverse effect of high iron intake. Show more

Keywords: Adults, Chinese, cognition, iron intake, tea consumption

DOI: 10.3233/JAD-220344

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 271-282, 2022