Journal of Alzheimer's Disease - Volume 101, issue 1

Authors: Zhang, Yahui | Li, Yulin | Song, Shangchen | Li, Zhigang | Lu, Minggen | Shan, Guogen

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) patients are at a high risk of developing Alzheimer’s disease and related dementias (ADRD) at an estimated annual rate above 10%. It is clinically and practically important to accurately predict MCI-to-dementia conversion time. Objective: It is clinically and practically important to accurately predict MCI-to-dementia conversion time by using easily available clinical data. Methods: The dementia diagnosis often falls between two clinical visits, and such survival outcome is known as interval-censored data. We utilized the semi-parametric model and the random forest model for interval-censored data in conjunction with a variable selection approach …to select important measures for predicting the conversion time from MCI to dementia. Two large AD cohort data sets were used to build, validate, and test the predictive model. Results: We found that the semi-parametric model can improve the prediction of the conversion time for patients with MCI-to-dementia conversion, and it also has good predictive performance for all patients. Conclusions: Interval-censored data should be analyzed by using the models that were developed for interval- censored data to improve the model performance. Show more

Keywords: Alzheimer’s disease, interval-censored data, MCI-to-dementia conversion, model selection, random forest, survival data

DOI: 10.3233/JAD-240285

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 147-157, 2024

Authors: Chen, Jun | Yang, Jingwen | Shen, Dayong | Wang, Xi | Lin, Zihao | Chen, Hao | Cui, Guiyun | Zhang, Zuohui

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a heterogeneous condition that can precede various forms of dementia, including Alzheimer’s disease (AD). Identifying MCI subjects who are at high risk of progressing to AD is of major clinical relevance. Enlarged perivascular spaces (EPVS) on MRI are linked to cognitive decline, but their predictive value for MCI to AD progression is unclear. Objective: This study aims to assess the predictive value of EPVS for MCI to AD progression and develop a predictive model combining EPVS grading with clinical and laboratory data to estimate conversion risk. Methods: We analyzed 358 …patients with MCI from the ADNI database, consisting of 177 MCI-AD converters and 181 non-converters. The data collected included demographic information, imaging data (including perivascular spaces grade), clinical assessments, and laboratory test results. Variable selection was conducted using the Least Absolute Shrinkage and Selection Operator (LASSO) method, followed by logistic regression to develop predictive model. Results: In the univariate logistic regression analysis, both moderate (OR = 5.54, 95% CI [3.04–10.18]) and severe (OR = 25.04, 95% CI [10.07–62.23]) enlargements of the centrum semiovale perivascular space (CSO-PVS) were found to be strong predictors of disease progression. LASSO analyses yielded 12 variables, refined to six in the final model: APOE4 genotype, ADAS11 score, CSO-PVS grade, and volumes of entorhinal, fusiform, and midtemporal regions, with an AUC of 0.956 in the training and 0.912 in the validation cohort. Conclusions: Our predictive model, emphasizing EPVS assessment, provides clinicians with a practical tool for early detection and management of AD risk in MCI patients. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, nomogram, perivascular space

DOI: 10.3233/JAD-240523

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 159-173, 2024

Authors: Ogbuagu, Chukwuanugo | Ogbuagu, Ekenechukwu | Emelumadu, Obiageli | Okereke, Uzoma | Okeke, Irene | Chigbo, Godswill | Javendal, Shireen | Miller, Bruce | Valcour, Victor | Allen, Isabel Elaine | Goode, Collette | Possin, Katherine L. | Uwakwe, Richard

Article Type: Research Article

Abstract: Background: Cognitive assessment is a key component of clinical evaluations for patients with dementia and Alzheimer’s disease in primary health care (PHC) settings. The need for well-validated, culturally appropriate, and easy-to-use assessments is especially urgent in low- and middle-income countries (LMICs) that are experiencing rapid growth in their older adult populations. Objective: To examine the feasibility and demographic determinants of performance for a tablet-based cognitive assessment tool (TabCAT) battery, which includes subtests for four cognitive domains, among older PHC patients in southeastNigeria. Methods: A cross-sectional mixed-method descriptive study evaluating the useability and performance of TabCAT. …Results: We enrolled 207 participants (mean age of 64.7±13.5 years; 52% with only primary, 41% secondary, and 7% tertiary education). Most (91%) who initiated the assessment were able to complete it, requiring 10–15 minutes to complete. More years of education was associated with better test scores across all tests (p  < 0.001). Living in a rural location was also associated with better performance (p  < 0.05). Male compared to female sex did not associate with performance on any of the tests (all ps > 0.05). Conclusions: Tablet-based cognitive assessment was feasible in rural and urban settings of Nigeria. Better performance on cognitive subtests linked to more education and residing in a rural area; however, sex did not predict performance. Digital cognitive assessment tools hold potential for widespread use in healthcare and educational contexts, particularly in regions with varying levels of urbanization and educational access. Show more

Keywords: Alzheimer’s disease, cognitive assessment, dementia, Nigeria, primary healthcare

DOI: 10.3233/JAD-240518

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 175-182, 2024

Authors: Zhang, Junyao | Zhang, Yinglin | Zhang, Yingying | Yao, Junyan

Article Type: Research Article

Abstract: Background: Our previous studies indicated that anesthesia/surgery could aggravate cognitive impairment and tau pathology in female 5XFAD transgenic (Tg) mice. However, it is unknown whether there are sex differences in the susceptibility of developing postoperative cognitive dysfunction in 5XFAD Tg mice. Objective: In this study, we aim to determine whether anesthesia/surgery can have different effects on female and male 5XFAD Tg mice, and to explore the underpinning mechanisms. Methods: The mice received abdominal surgery under isoflurane anesthesia. Morris water maze was used to assess the cognitive function. Hippocampal levels of p-tau (AT8), p-IRS1 (Ser612), IRS1, p-GSK3β …(Tyr216), and p-GSK3β (Ser9) at postoperative day 1 were evaluated by western blot assays. Results: Anesthesia/surgery exaggerated cognitive impairment and tau pathology in female, but not male 5XFAD Tg mice. The anesthesia/surgery led to elevated hippocampus protein levels of p-IRS1 (Ser612)/IRS1 ratio and p-GSK3β (Tyr216) and reduced hippocampus protein levels of p-GSK3β (Ser9) in female, but not male 5XFAD Tg mice. Conclusions: This study demonstrated that female 5XFAD Tg mice were more susceptible to anesthesia/surgery-induced cognitive deterioration and tau pathology aggravation, potentially due to female-specific brain insulin resistance. Show more

Keywords: Alzheimer’s disease, anesthesia/surgery, brain insulin resistance, cognitive dysfunction, sex difference, tau

DOI: 10.3233/JAD-231444

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 183-195, 2024

Authors: Cui, Xiaoyan | Wang, Junqiao | Tang, Xueting | Ding, Ding | Wu, Bei | Zhao, Qianhua | Wang, Jing

Article Type: Research Article

Abstract: Background: Young-onset dementia (YOD) refers to dementia occurring before the age of 65, with Alzheimer’s disease being the most common form, posing distinct challenges for spousal caregivers. Objective: This study aims to investigate the unique experiences of spousal caregivers of persons with YOD in China, where dementia-specific community care services and primary healthcare professionals are relatively lacking, in order to inform the tailored support services development. Methods: This qualitative-design study utilized semi-structured interviews with 11 spousal caregivers of persons with YOD dwelling in the community. Traditional content analysis was employed to analyze the interview data. …Results: Limited dementia-specific healthcare professionals and low public awareness made diagnosing and accepting YOD a prolonged and challenging journey. Spousal caregivers faced skepticism when seeking diagnosis, exacerbating their burden and emotional stress. Disparities in healthcare professionals and insufficient collaboration between institutions worsened the situation. YOD significantly impacted family dynamics and led to changes in emotional communication within the family. The stigma surrounding YOD raised concerns among spousal caregivers about their children’s future in marriage and career, emphasizing genetic risks. Conclusions: In settings where dementia-specific community care services and primary healthcare professionals are limited and unevenly distributed, integrating support services at both the primary and community levels is crucial for families dealing with YOD in the community. Additionally, raising public awareness about YOD can foster a more understanding and supportive environment, addressing challenges related to stigma faced by affected families, contributing to increased investment in supporting resources, and encouraging individuals to seek help early on. Show more

Keywords: Alzheimer’s disease, caregiving experiences, challenges, spousal caregiver, young-onset dementia

DOI: 10.3233/JAD-240249

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 197-209, 2024

Authors: Rustamzadeh, Auob | Tafakhori, Abbas | Ariaei, Armin | Heydari, Mahdi | Shah-abadi, Mehran Ebrahimi | Seif, Farhad

Article Type: Research Article

Abstract: Background: Laminopathy is a pathological manifestation observed in Alzheimer’s disease (AD), leading to neuronal apoptosis. Objective: Our objective was to assess inhibitors of enzymes involved in laminopathy. Methods: The mRNA expression of the cathepsins L and B, caspases 3 and 6, lamins b1 and b2, granzymes A and B, and lamins A and C were extracted and analyzed from GSE5281 and GSE28146 datasets. A total of 145 ligands were selected for molecular docking. Subsequently, 10 ns and 100 ns atomistic molecular dynamics (MD) and Martini 3 were performed with NAMD for two selected ligands (PubChem id: 608841 and …ChEMBL id: 550872). Results: The mRNA expression level highlighted caspase 6 and lamin A/C upregulation in the hippocampus of the AD samples, in contrast to cathepsin B, lamin b2, and caspase 3. Moreover, there was a strong correlation between the expression level of cathepsin B, lamin A/C, and caspase 6 in the AD group. The MD results suggested molecule with ChEMBL id of 550872 had higher free binding energy, while in longer simulation the molecule with PubChem id of 608841 was suggested to be more stable in complex with the receptor. Conclusions: Our findings suggest that lamins A/C, cathepsins B/L, caspase 6, and lamin B2 are associated with laminopathy as potential factors contributing to apoptosis in AD. We propose that simultaneous inhibition of caspases 6 and cathepsins L may decrease the rate of apoptosis triggered by lamin degradation. Nevertheless, further studies are required to confirm these observations due to the lack of in vivo findings. Show more

Keywords: Alzheimer’s disease, laminopathy, molecular dynamics, transcriptome

DOI: 10.3233/JAD-240413

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 211-221, 2024

Authors: Engedal, Knut | Benth, Jūratė Šaltytė | Wagle, Jørgen | Gjøra, Linda | Selbæk, Geir | Persson, Karin

Article Type: Research Article

Abstract: Background: The Clock Drawing Test (CDT) is used to screen for Alzheimer’s disease and other dementia disorders. Normative scores on the version from the Montreal Cognitive Assessment (MoCA) do not exist in the Nordic countries. Objective: To examine the normative scores of the CDT among adults aged 70 years and older. Methods: We included 4,023 cognitively healthy persons aged 70–97 years from a population survey in Norway. They were examined with the CDT, which has a total score between zero and three. A multiple multinominal regression model was applied with a CDT score as the dependent …categorical variable and estimated the probabilities of scoring a particular score, stratified by age, sex, and education. These probabilities correspond to an expected proportion of the normative population scoring at, or below a given percentile. Results: None scored zero, 2.1% scored one, 14.9% scored two, and 83% scored three. Higher age, female sex and fewer years of schooling were associated with poorer performance. Scores of zero and one deviated from the normative score regardless of age, sex and education. A score of two was within the norm for a female older than 81 and a male older than 85. Conclusions: The majority (83%) of people 70 years and older had a score of three on the CDT. Lower age, male sex, and higher education were associated with a better performance. Scores of zero and one were below the normative score. Except for the very old, a score of two was also well below the normative score. Show more

Keywords: Alzheimer’s disease, Clock Drawing Test, cognitive impairment, dementia, normative score

DOI: 10.3233/JAD-231331

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 223-234, 2024

Authors: Fan, Meixiang | Li, Qingfeng | Yang, Tingting | Yang, Yinghua | Chen, Zhihua | Xuan, Guo | Ruan, Ye | Sun, Shuangyuan | Wang, Meng | Chen, Xiaoli | Huang, Yanyan | Yang, Zhi | Wang, Ying

Article Type: Research Article

Abstract: Background: Previous trials have indicated that multimodal training could improve cognitive functions and moods in individuals with mild cognitive impairment (MCI). However, evidence was mainly obtained from studies in high-income countries. Objective: This trial aims to investigate the efficacy, safety, and potential mechanism of a multimodal intervention on cognitive function in individuals with MCI living in a community. Methods: In this single-blind, randomized controlled trial, 120 participants with MCI were randomly assigned to either the intervention group or the control group. The intervention group received the multimodal intervention, while the control group received regular health education. …Neuropsychological tests and magnetic resonance imaging (MRI) were conducted at baseline and after the 12-week intervention. Results: Fifty-nine and fifty-seven participants respectively in the intervention and control groups completed the trial. The intervention group shown improvements in primary outcome, Mini-Mental State Exam (MMSE) total score (mean difference –0.96, 95% CI [–1.58, –0.34], p  = 0.003), and secondary outcomes: MMSE recall (–0.39, 95% CI [–0.71, –0.07], p  = 0.019), MMSE language (–0.26, 95% CI [–0.44, –0.07], p  = 0.007), Auditory Verbal Learning Test instantaneous memory (–3.30, 95% CI [–5.70, –0.89], p  = 0.008), Digit Symbol Substitution Test total score (–2.91, 95% CI [–5.67, –0.15], p  = 0.039), digit span forwards (–1.25, 95% CI [–1.93, –0.56], p  < 0.001), and Digit Span Test (–1.33, 95% CI [–2.33, –0.34], p  = 0.009) compared to the control group. Improvements were observed in structural and functional connectivity related to language, concentration, executive function, memory, and recall functioning via MRI in the intervention group. Conclusions: The multimodal intervention improved cognitive function in individuals with MCI in cognitive performance and neuroimaging. Show more

Keywords: Alzheimer’s disease, behavior therapy, clinical trial, cognitive dysfunction

DOI: 10.3233/JAD-231370

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 235-248, 2024

Authors: Avelar-Pereira, Bárbara | Phillips, Curran Michael | Hosseini, S. M. Hadi

Article Type: Research Article

Abstract: Background: Age represents the largest risk factor for Alzheimer’s disease (AD) but is typically treated as a covariate. Still, there are similarities between brain regions affected in AD and those showing accelerated decline in normal aging, suggesting that the distinction between the two might fall on a spectrum. Objective: Our goal was to identify regions showing accelerated atrophy across the brain and investigate whether these overlapped with regions involved in AD or where related to amyloid. Methods: We used a longitudinal sample of 137 healthy older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), who underwent …magnetic resonance imaging (MRI). In addition, a total of 79 participants also had longitudinal positron emission tomography (PET) data. We computed linear-mixed effects models for brain regions declining faster than the average to investigate variability in the rate of change. Results: 23 regions displayed a 0.5 standard deviation (SD) above average decline over 2 years. Of these, 52% overlapped with regions showing similar decline in a matched AD sample. Beyond this, the left precuneus, right superior frontal, transverse temporal, and superior temporal sulcus showed accelerated decline. Lastly, atrophy in the precuneus was associated with increased amyloid load. Conclusions: Accelerated decline in normal aging might contribute to the detection of early signs of AD among healthy individuals. Show more

Keywords: Accelerated atrophy, Alzheimer’s disease, amyloid acculumation, gray matter, normal aging

DOI: 10.3233/JAD-231458

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 249-258, 2024

Authors: Nataraj, Athira | Kala, Annu | Proskauer Pena, Stephanie Lissette | Jezek, Karel | Blahna, Karel

Article Type: Research Article

Abstract: Background: The hippocampal representation of space, formed by the collective activity of populations of place cells, is considered as a substrate of spatial memory. Alzheimer’s disease (AD), a widespread severe neurodegenerative condition of multifactorial origin, typically exhibits spatial memory deficits among its early clinical signs before more severe cognitive impacts develop. Objective: To investigate mechanisms of spatial memory impairment in a double transgenic rat model of AD. Methods: In this study, we utilized 9–12-month-old double-transgenic TgF344-AD rats and age-matched controls to analyze the spatial coding properties of CA1 place cells. We characterized the spatial memory representation, …assessed cells’ spatial information content and direction-specific activity, and compared their population coding in familiar and novel conditions. Results: Our findings revealed that TgF344-AD animals exhibited lower precision in coding, as evidenced by reduced spatial information and larger receptive zones. This impairment was evident in maps representing novel environments. While controls instantly encoded directional context during their initial exposure to a novel environment, transgenics struggled to incorporate this information into the newly developed hippocampal spatial representation. This resulted in impairment in orthogonalization of stored activity patterns, an important feature directly related to episodic memory encoding capacity. Conclusions: Overall, the results shed light on the nature of impairment at both the single-cell and population levels in the transgenic AD model. In addition to the observed spatial coding inaccuracy, the findings reveal a significantly impaired ability to adaptively modify and refine newly stored hippocampal memory patterns. Show more

Keywords: Alzheimer’s disease, place cell directionality, place field size, spatial memory, TgF344-AD rats

DOI: 10.3233/JAD-231386

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 259-276, 2024