Journal of Alzheimer's Disease - Volume 97, issue 4

Authors: Ferini-Strambi, Luigi

Article Type: Article Commentary

Abstract: Sleep disorders can represent an independent risk factor for cognitive decline and Alzheimer’s disease (AD). It remains to be clarified if specific sleep parameters could be considered biomarkers of AD-related neurodegeneration. Several studies solely investigated the results of cross-sectional research, without providing conclusive evidence. Few longitudinal studies showed some inconsistencies in macrostructural and microstructural sleep findings. Methodological heterogeneity among studies can explain the discrepancies in the results. Moreover, the polysomnographic findings are usually related to only one-night recording. The combination of actigraphic recordings with sleep EEG monitoring for some consecutive days should be considered in future research.

Keywords: Alzheimer’s disease, biomarkers, cognitive decline, sleep

DOI: 10.3233/JAD-231311

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1641-1643, 2024

Authors: Jiao, Liyuan | Jing, Ziye | Zhang, Wenjie | Su, Xuesen | Yan, Hualei | Tian, Shouyuan

Article Type: Research Article

Abstract: Background: Previous reports have demonstrated post-operative dementia and Alzheimer’s disease (AD), and increased amyloid-β levels and tau hyperphosphorylation have been observed in animal models post-anesthesia. Objective: After surgical interventions, loss in memory has been observed that has been found linked with genes modulated after anesthesia. Present study aimed to study molecular pattern present in genes modulated post anesthesia and involved in characters progressing towards AD. Methods: In the present study, 17 transcript variants belonging to eight genes, which have been found to modulate post-anesthesia and contribute to AD progression, were envisaged for their compositional features, molecular …patterns, and codon and codon context-associated studies. Results: The sequences’ composition was G/C rich, influencing dinucleotide preference, codon preference, codon usage, and codon context. The G/C nucleotides being highly occurring nucleotides, CpGdinucleotides were also preferred; however, CpG was highly disfavored at p3-1 at the codon junction. The nucleotide composition of Cytosine exhibited a unique feature, and unlike other nucleotides, it did not correlate with codon bias. Contrarily, it correlated with the sequence lengths. The sequences were leucine-rich, and multiple leucine repeats were present, exhibiting the functional role of neuroprotection from neuroinflammation post-anesthesia. Conclusions: The analysis pave the way to elucidate unique molecular patterns in genes modulated during anesthetic treatment and might help ameliorate the ill effects of anesthetics in the future. Show more

Keywords: Alzheimer’s disease, anesthesia, CpG overrepresentation, codon context, gene modulation, tau aggregation

DOI: 10.3233/JAD-231142

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1645-1660, 2024

Authors: Chen, Lihua | Zhang, Meiwei | Yu, Weihua | Yu, Juan | Cui, Qiushi | Chen, Chenxi | Liu, Junjin | Huang, Lihong | Liu, Jiarui | Yu, Wuhan | Li, Wenjie | Zhang, Wenbo | Yan, Mengyu | Wu, Jiani | Wang, Xiaoqin | Song, Jiaqi | Zhong, Fuxing | Liu, Xintong | Wang, Xianglin | Li, Chengxing | Tan, Yuantao | Sun, Jiangshan | Li, Wenyuan | Lü, Yang

Article Type: Research Article

Abstract: Background: Rapidly growing healthcare demand associated with global population aging has spurred the development of new digital tools for the assessment of cognitive performance in older adults. Objective: To develop a fully automated Mini-Mental State Examination (MMSE) assessment model and validate the model’s rating consistency. Methods: The Automated Assessment Model for MMSE (AAM-MMSE) was an about 10-min computerized cognitive screening tool containing the same questions as the traditional paper-based Chinese MMSE. The validity of the AAM-MMSE was assessed in term of the consistency between the AAM-MMSE rating and physician rating. Results: …A total of 427 participants were recruited for this study. The average age of these participants was 60.6 years old (ranging from 19 to 104 years old). According to the intraclass correlation coefficient (ICC), the interrater reliability between physicians and the AAM-MMSE for the full MMSE scale AAM-MMSE was high [ICC (2,1)=0.952; with its 95% CI of (0.883,0.974)]. According to the weighted kappa coefficients results the interrater agreement level for audio-related items showed high, but for items “Reading and obey”, “Three-stage command”, and “Writing complete sentence” were slight to fair. The AAM-MMSE rating accuracy was 87%. A Bland-Altman plot showed that the bias between the two total scores was 1.48 points with the upper and lower limits of agreement equal to 6.23 points and −3.26 points. Conclusions: Our work offers a promising fully automated MMSE assessment system for cognitive screening with pretty good accuracy. Show more

Keywords: Alzheimer’s disease, automated assessment, cognitive function, computer-related technologies, cognitive screening, Mini-Mental State Examination

DOI: 10.3233/JAD-230518

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1661-1672, 2024

Authors: Okinaka, Yuka | Shinagawa, Yoshiyuki | Claussen, Carsten | Gul, Sheraz | Matsui, Ikuko | Matsui, Yutaka | Taguchi, Akihiko

Article Type: Research Article

Abstract: Background: One of the key symptoms of Alzheimer’s disease (AD) is the impairment of short-term memory. Hippocampal neurogenesis is essential for short-term memory and is known to decrease in patients with AD. Impaired short-term memory and impaired neurogenesis are observed in aged mice alongside changes in RNA expression of gap junction and metabolism-related genes in circulating leukocytes. Moreover, after penetrating the blood-brain barrier via the SDF1/CXCR4 axis, circulating leukocytes directly interact with hippocampal neuronal stem cells via gap junctions. Objective: Evaluation of RNA expression profiles in circulating leukocytes in patients with AD. Methods: …Patients with AD (MMSE≧23, n  = 10) and age-matched controls (MMSE≧28, n  = 10) were enrolled into this study. RNA expression profiles of gap junction and metabolism-related genes in circulating leukocytes were compared between the groups (jRCT: 1050210166). Results: The ratios of gap junction and metabolism-related genes were significantly different between patients with AD and age-matched controls. However, due to large inter-individual variations, there were no statistically significant differences in the level of single RNA expression between these groups. Conclusions: Our findings suggest a potential connection between the presence of circulating leukocytes and the process of hippocampal neurogenesis in individuals with AD. Analyzing RNA in circulating leukocytes holds promise as a means to offer novel insights into the pathology of AD, distinct from conventional markers. Show more

Keywords: Alzheimer’s disease, circulating leukocyte, gap junction, novel biomarker, quantitative PCR, white blood cells

DOI: 10.3233/JAD-230874

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1673-1683, 2024

Authors: Mone, Pasquale | De Luca, Antonio | Kansakar, Urna | Santulli, Gaetano

Article Type: Article Commentary

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder marked by amyloid-β accumulation, tau dysfunction, and neuroinflammation, involving endothelial cells and leukocytes. The breakdown of the blood-brain barrier allows immune cell infiltration, intensifying inflammation. A decreased ratio of Connexin-37 (Cx37, also known as GJA4: Gap Junction Protein Alpha 4) and Prolyl Hydroxylase Domain-Containing Protein 3 (PHD3, also known as EGLN3: Egl-9 Family Hypoxia Inducible Factor 3), Cx37/PHD3, consistently observed in different AD-related models, may represent a novel potential biomarker of AD, albeit the exact mechanisms underlying this phenomenon, most likely based on gap junction-mediated cellular interaction that modulate the cellular metabolite status, …remain to be fully elucidated. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, Cx37, endothelial cells, inflammation, PHD3

DOI: 10.3233/JAD-231464

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1685-1687, 2024

Authors: Posis, Alexander Ivan B. | Shadyab, Aladdin H. | Parada Jr., Humberto | Alcaraz, John E. | Kremen, William S. | McEvoy, Linda K.

Article Type: Research Article

Abstract: Background: Multimorbidity is associated with increased rate of cognitive decline with age. It is unknown whether social engagement, which is associated with reduced risk of dementia, modifies associations between multimorbidity and cognitive decline. Objective: To examine the associations of multimorbidity with longitudinal cognitive test performance among community-dwelling older adults, and to determine whether associations differed by levels of social engagement. Methods: We used data from the Rancho Bernardo Study of Healthy Aging, a community-based prospective cohort study. Starting in 1992–1996, participants completed a battery of cognitive function tests at up to 6 study visits over 23.7 …(mean = 7.2) years. Multimorbidity was defined as≥2 of 14 chronic diseases. Social engagement was assessed using items based on the Berkman-Syme Social Network Index. Multivariable linear mixed-effects models were used to test associations of multimorbidity and cognitive performance trajectories. Effect measure modification by social engagement was evaluated. Results: Among 1,381 participants (mean age = 74.5 years; 60.8% women; 98.8% non-Hispanic White), 37.1% had multimorbidity and 35.1% had low social engagement. Multimorbidity was associated with faster declines in Mini-Mental State Examination (MMSE; β= –0.20; 95% CI –0.35, –0.04), Trail-Making Test Part B (β= 10.02; 95% CI 5.77, 14.27), and Category Fluency (β= –0.42; 95% CI –0.72, –0.13) after adjustment for socio-demographic and health-related characteristics. Multimorbidity was associated with faster declines in MMSE among those with low compared to medium and high social engagement (p- interaction < 0.01). Conclusions: Multimorbidity was associated with faster declines in cognition among community-dwelling older adults. Higher social engagement may mitigate multimorbidity-associated cognitive decline. Show more

Keywords: Alzheimer’s disease, cognitive aging, epidemiology, morbidity, multimorbidities

DOI: 10.3233/JAD-230809

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1689-1702, 2024

Authors: de la Monte, Suzanne M. | Tong, Ming

Article Type: Research Article

Abstract: Background: Agent Orange (AO) is a Vietnam War-era herbicide that contains a 1 : 1 ratio of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Emerging evidence suggests that AO exposures cause toxic and degenerative pathologies that may increase the risk for Alzheimer’s disease (AD). Objective: This study investigates the effects of the two main AO constituents on key molecular and biochemical indices of AD-type neurodegeneration. Methods: Long Evans rat frontal lobe slice cultures treated with 250μg/ml of 2,4-D, 2,4,5-T, or both (D  + T) were evaluated for cytotoxicity, oxidative injury, mitochondrial function, and AD biomarker expression. Results: …Treatment with the AO constituents caused histopathological changes corresponding to neuronal, white matter, and endothelial cell degeneration, and molecular/biochemical abnormalities indicative of cytotoxic injury, lipid peroxidation, DNA damage, and increased immunoreactivity to activated Caspase 3, glial fibrillary acidic protein, ubiquitin, tau, paired-helical filament phosphorylated tau, AβPP, Aβ, and choline acetyltransferase. Nearly all indices of cellular injury and degeneration were more pronounced in the D  + T compared with 2,4-D or 2,4,5-T treated cultures. Conclusions: Exposures to AO herbicidal chemicals damage frontal lobe brain tissue with molecular and biochemical abnormalities that mimic pathologies associated with early-stage AD-type neurodegeneration. Additional research is needed to evaluate the long-term effects of AO exposures in relation to aging and progressive neurodegeneration in Vietnam War Veterans. Show more

Keywords: Agent Orange, Alzheimer’s disease, brain, herbicide, neurodegeneration, neurons, pesticide, Vietnam Veterans, white matter, 2, 4-D, 2, 4, 5-T

DOI: 10.3233/JAD-230881

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1703-1726, 2024

Authors: Leow, Yi Jin | Soo, See Ann | Kumar, Dilip | Zailan, Fatin Zahra Binte | Sandhu, Gurveen Kaur | Vipin, Ashwati | Lee, Faith Phemie Hui En | Ghildiyal, Smriti | Liew, Shan Yao | Dang, Chao | Tanoto, Pricilia | Tan, Isabelle Yu Zhen | Chong, Wayne Freeman Weien | Mohammed, Adnan Azam | Ng, Kok Pin | Kandiah, Nagaendran

Article Type: Research Article

Abstract: Background: Mild behavioral impairment (MBI) is one of the earliest observable changes when a person experiences cognitive decline and could be an early manifestation of underlying Alzheimer’s disease neuropathology. Limited attention has been given to investigating the clinical applicability of behavioral biomarkers for detection of prodromal dementia. Objective: This study compared the prevalence of self-reported MBI and vascular risk factors in Southeast Asian adults to identify early indicators of cognitive impairment and dementia. Methods: This cohort study utilized baseline data from the Biomarkers and Cognition Study, Singapore (BIOCIS). 607 participants were recruited and classified into three …groups: cognitively normal (CN), subjective cognitive decline (SCD), and mild cognitive impairment (MCI). Group comparisons of cognitive-behavioral, neuroimaging, and blood biomarkers data were applied using univariate analyses. Multivariate logistic regression analyses were conducted to investigate the association between cerebrovascular disease, vascular profiles, and cognitive impairment. Results: SCD had significantly higher depression scores and poorer quality of life (QOL) compared to CN. MCI had significantly higher depression scores; total MBI symptoms, MBI-interest, MBI-mood, and MBI-beliefs; poorer sleep quality; and poorer QOL compared to CN. Higher Staals scores, glucose levels, and systolic blood pressure were significantly associated with MCI classification. Fasting glucose levels were significantly correlated with depression, anxiety, MBI-social, and poorer sleep quality. Conclusions: The results reflect current research that behavioral changes are among the first symptoms noticeable to the person themselves as they begin to experience cognitive decline. Self-reported questionnaires may aid in early diagnoses of prodromal dementia. Behavioral changes and diabetes could be potential targets for preventative healthcare for dementia. Show more

Keywords: Alzheimer’s disease, biomarkers, diabetes, mild behavioral impairment, mild cognitive impairment

DOI: 10.3233/JAD-230898

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1727-1735, 2024

Authors: Zhang, Shengnan | Ai, Hongrui | Wang, Jia | Liu, Tiaotiao | Zheng, Xuyuan | Tian, Xin | Bai, Wenwen

Article Type: Research Article

Abstract: Background: Working memory deficits in Alzheimer’s disease (AD) are linked to impairments in the retrieval of stored memory information. However, research on the mechanism of impaired working memory retrieval in Alzheimer’s disease is still lacking. Objective: The medial prefrontal cortex (mPFC) and mediodorsal thalamus (MD) are involved in memory retrieval. The purpose of this study is to investigate the functional interactions and information transmission between mPFC and MD in the AD model. Methods: We recorded local field potentials from mPFC and MD while the mice (APP/PS1 transgenic model and control) performed a T-maze spatial working memory …task. The temporal dynamics of oscillatory activity and bidirectional information flow between mPFC and MD were assessed during the task phases. Results: We mainly found a significant decrease in theta flow from mPFC to MD in APP/PS1 mice during retrieval. Conclusions: Our results indicate an important role of the mPFC-MD input for retrieval and the disrupted information transfer from mPFC to MD may be the underlying mechanism of working memory deficits in APP/PS1 mice. Show more

Keywords: Alzheimer’s disease, information flow, local field potentials, medial prefrontal cortex, mediodorsal thalamus, spatial working memory

DOI: 10.3233/JAD-231078

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1737-1749, 2024

Authors: Ng, Pei Y. | Zhang, Cheng | Li, Hu | Baker, Darren J.

Article Type: Research Article

Abstract: Background: Cellular senescence has been associated with neurodegenerative disease and clearance of senescent cells using genetic or pharmaceutical strategies (senolytics) has demonstrated beneficial effects in mouse models investigating individual disease etiologies of Alzheimer’s disease (AD). However, it has remained unclear if senescent cell clearance in a mouse model exhibiting both plaque and tau pathologies modifies the disease state (3xTg). Objective: To investigate the effects of senescent cell clearance in the 3xTg mouse model. Methods: 3xTg mice were treated with senolytics (ABT263 (navitoclax; NAVI), a combination of dasatinib and quercetin (D+Q)), or subjected to transgene-mediated removal of …p16-expressing cells (via INK-ATTAC). Results: Senolytic treatments consistently reduced microgliosis and ameliorated both amyloid and tau pathology in 3xTg mice. Using RNA sequencing, we found evidence that synaptic dysfunction and neuroinflammation were attenuated with treatment. These beneficial effects were not observed with short-term senolytic treatment in mice with more advanced disease. Conclusions: Overall, our results further corroborate the beneficial effects senescent cell clearance could have on AD and highlight the importance of early intervention for the treatment of this debilitating disease. Show more

Keywords: Alzheimer’s disease, amyloid-β , cellular senescence, tauopathy

DOI: 10.3233/JAD-230465

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1751-1763, 2024