bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating adipokines and MRI markers of brain aging in middle-aged adults from the community
Authors: Satizabal Claudia L , Himali Jayandra Jung , Conner Sarah C , Beiser Alexa S , Maillard Pauline , Vasan Ramachandran S , DeCarli Charles , Seshadri Sudha 
Published: November 2024

Background Midlife obesity is related to late-onset dementia. Studying adipose tissue-secreted adipokines in the context of brain aging may help us understand this association. Objective To investigate associations between adipokines and brain MRI markers in middle-aged adults from the Third-Generation cohort of the Framingham Heart Study. Methods Serum adiponectin, retinol-binding protein 4 (RBP4), fetuin-A, and Fatty Acid-Binding Protein 4 (FABP4) concentrations were measured by enzymatic immunoassays. MRI measures included total brain, cortical gray matter, hippocampal (total and anterior), lateral ventricular, and white matter hyperintensity volumes. We used linear regression models to separately relate adipokine concentrations to MRI measures, adjusting for potential confounders. Results We included 1882 participants (mean age of 48 ± 8 years, 54% women). Higher RBP4 concentrations were related to markers of brain atrophy, including smaller total (Beta ± standard error, −0.05 ± 0.02; p = 0.014) and cortical gray brain volumes (−0.06 ± 0.02; p = 0.004), and larger lateral ventricular volumes (0.06 ± 0.02; p = 0.006). Additionally, higher RBP4 (−0.06 ± 0.03; p = 0.042), Fetuin-A (−0.06 ± 0.03; p = 0.039), and FABP4 (−0.09 ± 0.03; p = 0.008) concentrations were associated with smaller anterior hippocampal volumes. Most associations remained after additional adjustment for vascular risk factors. In exploratory analyses, higher FABP4 was related to larger total brain in non-obese participants, and to smaller anterior hippocampal volumes in obese participants. Finally, higher adiponectin concentrations were related to smaller cortical gray, only in non-obese participants. Conclusions Our results suggest that adipokines are associated with markers of brain atrophy during midlife. Further studies are needed to replicate these findings and elucidate any potential mechanisms contributing to abnormal brain aging.
Voluntary wheel running decreases amyloidogenic pathway and rescues cognition and mitochondrial energy metabolism in middle-aged female 3xTg-AD mouse model of Alzheimer's disease
Authors: dos Santos Jonathas Rodrigo , Catalão Carlos Henrique Rocha , Vulczak Anderson , Azzolini Ana Elisa Caleiro Seixas , Alberici Luciane Carla 
Published: November 2024

Background Evidence supports the neuroprotective effects of physical activity, either in experimental animal models or humans. However, the biological mechanisms by which physical exercise modulates dementia and Alzheimer's disease (AD) progression are still unclear. Objective This study investigated whether long-term (6 months) of voluntary wheel running induces neuroprotective effects in the pathogenesis of AD in middle-aged (8 months) female mice, focusing on energy metabolism. Methods A genetic mice model of AD (3xTg-AD) that performed wheel running presented changes in body metabolism and muscle oxidative profile, as well as restored discriminative and non-associative retention memories, evaluated by novel object recognition and open field tasks, respectively. Results In the hippocampus, these mice exhibited reduced levels of amyloidogenic AβPPβ fragment, phospho-Tau protein and phospho-Akt (activated form), without changes in phospho-AMPK (activated form). In addition, hippocampal mitochondria presented a restored respiratory function, characterized by lower coupling degree and weak contribution from complex I found in 3xTg-AD mice. Conclusions The results demonstrated that voluntary exercise improves cognitive parameters and biochemical hallmarks of AD, modulates Akt activation and enhances mitochondrial energy metabolism in hippocampus of middle-aged 3xTg-AD female mice, thereby reinforcing the neuroprotective role of physical exercise and the involvement of mitochondria in the etiology of the AD.
The safety and effectiveness of 40 Hz γ-tACS in Alzheimer's disease: A meta-analysis
Authors: Zhang Xinyang , Lv Renhua , Sun Yanqiu , Liu Timon Cheng-Yi 
Published: November 2024

Background The efficacy and safety of 40 Hz gamma transcranial alternating current stimulation (γ-tACS) in Alzheimer's disease (AD) are still uncertain. Objective This meta-analysis was conducted to investigate the therapeutic potential and safety of 40 Hz γ-tACS for AD. Methods The meta-analysis was conducted by systematically searching four databases from their start to 28 December 2023. Subgroup analyses were performed to identify the intervention effects of γ-tACS. Results Of the 7 included studies, γ-tACS has a notable impact on improving overall cognition [standardized mean difference (SMD): 0.49, 95% CI: 0.09 to 0.89], memory (SMD: 0.79, 95% CI: 0.18 to 1.41), and cholinergic transmission (weighted mean difference: −0.40, 95% CI: −0.43 to −0.37). Furthermore, subgroup analysis revealed that γ-tACS treatment had a substantial impact on enhancing memory targeting the left angular gyrus in both home (SMD: 3.12, 95% CI: 1.54 to 4.70) and non-home settings (SMD: 0.53, 95% CI: 0.24 to 0.82). However, γ-tACS had a positive effect on overall cognition in non-home settings (SMD: 0.55, 95% CI 0.11 to 0.98), but not in home settings (SMD: 0.22, 95% CI −0.76 to 1.20). Additionally, targeting temporo-frontal or bitemporal γ-tACS treatment resulted in improvement in overall cognition (SMD: 0.61, 95% CI: 0.06 to 1.16), but not targeting the left angular gyrus (SMD: 0.22, 95% CI: −0.76 to 1.20). Conclusions γ-tACS could be beneficial in enhancing cognition, memory and restoring cholinergic dysfunction in AD. The different selection of stimulation sites plays distinct roles. Meanwhile, AD patients are recommended to receive γ-tACS treatment at home.
The association between oral diseases and neurodegenerative disorders
Authors: Soiniemi Lauriina , Solje Eino , Suominen Anna Liisa , Kanninen Katja M , Kullaa Arja M 
Published: November 2024

Background The association between cognitive neurodegenerative disease and oral diseases has been under great interest recently. Several studies have suggested a connection between periodontitis and Alzheimer's disease (AD) or other neurodegenerative disorders. Objective This study aimed to review the potential mechanisms between oral diseases and neurodegenerative diseases. Methods The study was executed as a literature review of English-language publications from 2018–2022. The databases used for the search were PubMed, Cochrane, Scopus, and Web of Science. The search phrases used were “ neurodegenerative diseases” AND “ oral health” and “ neurodegenerative diseases” AND “ oral diseases.” Results The linkage between the two disease groups was observed in several distinct publications and several potential mechanisms were found. The link between periodontitis and AD proved to be the most significant. The effect was accentuated in elderly people where individuals possessed also other risk factors for neurodegenerative diseases and had generally worse oral health conditions. Conclusions Oral diseases may be risks for neurodegenerative changes along many different pathways. Good oral health should be acknowledged as a potential preventative or risk-reducing act against neurodegenerative diseases.
Exploring phytochemical inhibitors of protein kinase C alpha for therapeutic targeting of Alzheimer's disease
Authors: Aazad AA , Choudhury Arunabh , Hussain Afzal , AlAjmi Mohamed F , Mohammad Taj , Prabha Sneh , Sharma Manoj Kumar , Shamsi Anas , Hassan Md Imtaiyaz 
Published: November 2024

Background Alzheimer's disease (AD) is characterized by neurodegeneration linked to amyloid-β (Aβ) plaques and tau protein tangles. Protein kinase C alpha (PKCα) plays a crucial role in modulating amyloid-β protein precursor (AβPP) processing, potentially mitigating AD progression. Consequently, PKCα stands out as a promising target for AD therapy. Objective Despite the identification of numerous inhibitors, the pursuit of more effective and precisely targeted PKCα inhibitors remains crucial. Methods In this study, we employed an integrated virtual screening approach of molecular docking and molecular dynamics (MD) simulations to identify phytochemical inhibitors of PKCα from the IMPPAT database. Results Molecular docking screening via InstaDock identified compounds with strong binding affinities to PKCα. Subsequent ADMET and PASS analyses filtered out compounds with favorable pharmacokinetic profiles. Interaction analysis using Discovery Studio Visualizer and PyMOL further elucidated binding conformations of selected compounds with PKCα. Top hits underwent 200 ns MD simulations using GROMACS to validate stability of the interactions. Finally, we propose two phytochemicals, Kammogenin and Imperialine, with appreciable drug-likeliness and binding potential with PKCα. Conclusions Taken together, the findings suggest Kammogenin and Imperialine as potential PKCα inhibitors, highlighting their therapeutic promise for AD after further validation.
Amyloid-β positivity is less prevalent in cognitively unimpaired KLOTHO KL-VS heterozygotes
Authors: Cook Noah , Driscoll Ira , Gaitán Julian M , Glittenberg Matthew , Betthauser Tobey J , Carlsson Cynthia M , Johnson Sterling C , Asthana Sanjay , Zetterberg Henrik , Blennow Kaj , Kollmorgen Gwendlyn , Quijano-Rubio Clara , Dubal Dena B , Okonkwo Ozioma C 
Published: November 2024

Background Klotho, encoded by the KLOTHO gene, is an anti-aging and neuroprotective protein. KLOTHO KL-VS heterozygosity (KL-VSHET) is hypothesized to be protective against the accumulation of Alzheimer's disease (AD) neuropathological hallmarks (amyloid-β (Aβ) and tau). Objective We examine whether being positive for Aβ (A+) or tau (T+), or A/T joint status [positive for Aβ (A + T-), tau (A-T+), both (A + T+) or neither (A-T-)] vary by KL-VS and whether serum klotho protein levels vary based on A+, T+, or A/T status in a cohort enriched for AD risk. Methods The sample consisted of 704 cognitively unimpaired, late middle-aged, and older adults; MeanAge(SD) = 64.9(8.3). Serum klotho was available for a sub-sample of 396 participants; MeanAge(SD) = 66.8(7.4). Covariate-adjusted logistic regression examined whether A + or T+, and multinomial regression examined whether A/T status, vary by KL-VS genotype. Covariate-adjusted linear regression examined whether serum klotho levels differ based on A+, T+, or A/T status. Results A+ prevalence was lower in KL-VSHET ( p = 0.05), with no differences in T + prevalence ( p = 0.52). KL-VSHET also had marginally lower odds of being A + T- ( p = 0.07). Serum klotho levels did not differ based on A+, T+, or A/T status (all ps ≥ 0.40). Conclusions KL-VSHET is associated with lower odds of being positive for Aβ, regardless of whether one is also positive for tau. Conversely, the likelihood of being tau positive did not differ based on KL-VS genotype. Our findings add to the growing KLOTHO literature and suggests the need for further research focused on understanding the mechanisms underlying KL-VS-related putative resilience to AD.
Detecting functional impairment with the Digital Clock and Recall
Authors: Ciesla Marissa , Toro-Serey Claudio , Jannati Ali , Banks Russell E , Gomes-Osman Joyce , Showalter John , Bates David , Tobyne Sean , Pascual-Leone Alvaro 
Published: November 2024

Background Distinguishing between mild cognitive impairment (MCI) and early dementia requires both neuropsychological and functional assessment that often relies on caregivers’ insights. Contacting a patient's caregiver can be time-consuming in a physician's already-filled workday. Objective To assess the utility of a brief, machine learning (ML)-enabled digital cognitive assessment, the Digital Clock and Recall (DCR), for detecting functional dependence. Methods We evaluated whether the DCR can help identify individuals at risk of functional deficits as measured by the informant-rated Functional Activities Questionnaire (FAQ) in older individuals including cognitively unimpaired, MCI, and dementia likely due to Alzheimer's disease. Results The DCR scaled well with FAQ scores, and ML classifiers trained on multimodal DCR features demonstrated strong performance in predicting functional impairment on a held-out test set. Differences in FAQ scores between DCR-predicted classes were comparable across key demographic groups. Conclusions The DCR can streamline the clinical decision-making, triage, and intervention planning associated with functional impairment in primary care.
Estimating the rates of dementia using administrative data linked to cohort studies
Authors: Waller Michael , Flicker Leon , Fitzgerald Patrick , Almeida Osvaldo P , Anstey Kaarin J , Dobson Annette J 
Published: November 2024

Background Current estimates of dementia and Alzheimer's disease incidence and prevalence are required to understand the health needs of the elderly. Objective We used two Australia cohort studies, administrative datasets, and data linkage techniques to estimate dementia rates in Australia. Methods The study used Australian Longitudinal Study on Women's Health and the Health in Men Cohort Study. Records of dementia were obtained from linked sources and incidence and prevalence estimates were produced. Capture-recapture methods were used to estimate numbers of dementia cases not identified through data linkage. Results There were 3399 (28.5%) men with dementia identified from any source and 3767 (34.8%) women. Rates of dementia incidence and prevalence were similar between sexes but were raised in men once estimates of unidentified cases were included. Conclusions Cohort studies and linked administrative data can be used together to produce current estimates of dementia prevalence and incidence comparable to other population estimates.
High frequency post-pause word choices and task-dependent speech behavior characterize connected speech in individuals with mild cognitive impairment
Authors: Kleiman Michael J , Galvin James E 
Published: November 2024

Background Alzheimer's disease (AD) is characterized by progressive cognitive decline, including impairments in speech production and fluency. Mild cognitive impairment (MCI), a prodrome of AD, has also been linked with changes in speech behavior but to a more subtle degree. Objective This study aimed to investigate whether speech behavior immediately following both filled and unfilled pauses (post-pause speech behavior) differs between individuals with MCI and healthy controls (HCs), and how these differences are influenced by the cognitive demands of various speech tasks. Methods Transcribed speech samples were analyzed from both groups across different tasks, including immediate and delayed narrative recall, picture descriptions, and free responses. Key metrics including lexical and syntactic complexity, lexical frequency and diversity, and part of speech usage, both overall and post-pause, were examined. Results Significant differences in pause usage were observed between groups, with a higher incidence and longer latencies following these pauses in the MCI group. Lexical frequency following filled pauses was higher among MCI participants in the free response task but not in other tasks, potentially due to the relative cognitive load of the tasks. The immediate recall task was most useful at differentiating between groups. Predictive analyses utilizing random forest classifiers demonstrated high specificity in using speech behavior metrics to differentiate between MCI and HCs. Conclusions Speech behavior following pauses differs between MCI participants and healthy controls, with these differences being influenced by the cognitive demands of the speech tasks. These post-pause speech metrics can be easily integrated into existing speech analysis paradigms.
Neurologic dance training and home exercise improve motor-cognitive dual-task function similarly, but through potentially different mechanisms, among breast cancer survivors with chemotherapy-induced neuropathy: Initial results of a randomized, controlled clinical trial
Authors: Worthen-Chaudhari Lise C. , Crasta Jewel E. , Schnell Patrick M. , Lantis Kristin , Martis Joseph , Wilder Jacqueline , Bland Courtney R. , Hackney Madeleine E. , Lustberg Maryam B. 
Published: November 2024

Background Dual-task function is compromised among individuals with prodromal Alzheimer's disease (AD) and others at risk of developing AD. While exercise has been studied as a therapeutic candidate, the activity of social dance might promote dual-task rehabilitation as well or better than conventional exercise. Objective Compare effects of social dance versus home exercise on dual-task function and intervention adherence among individuals with increased risk of developing AD: survivors of breast cancer (BC) with chemotherapy-induced neuropathy (CIN). Methods Fifty-two (n = 52) survivors of BC with CIN-related symptoms and functional deficits were randomized (1:1) to 8 weeks of biweekly physical activity that took the form of partnered AdapTango dance (20 min) or home exercise (45 min) (NCT05114005, registered 08/15/2021). Primary outcome: dual-task function (TUG-Cog counting backward by 3 s). Secondary outcome: adherence. Exploratory outcomes: participant rating of perceived exertion in physical versus cognitive domains and cognitive load during dual-task performance. Results Both interventions improved Timed-Up-and-Go with cognitive task (TUGCog) after 4 weeks ( p < 0.001); gains were maintained at 8 weeks of intervention ( p < 0.001) and 1 month follow-up ( p < 0.001). The dance intervention met adherence feasibility criteria for 8 weeks; exercise met criteria for 4 weeks. The ratio of cognitive to physical exertion was higher for dance (1 to 1) than exercise (0.8 to 1.0; p < 0.001). Dance, only, was associated with reduced cognitive load ( p = 0.02). Conclusions Among survivors of BC with CIN, small doses of social dance improved dual-task function comparably to larger doses of home exercise, possibly due to differences in cognitive engagement.
Associations among healthy lifestyle characteristics, neuroinflammation, and cerebrospinal fluid core biomarkers of Alzheimer's disease in cognitively intact adults: The CABLE study
Authors: Wang Lan-Yang , Hu Hao , Sheng Ze-Hu , Hu He-Ying , Zhang Zi-Hao , Tan Lan 
Published: November 2024

Background The occurrence of Alzheimer's disease (AD) can be partially prevented through healthy lifestyles, but the mechanisms associated with AD pathology are unclear. Objective To explore associations among healthy lifestyle characteristics (HLCs), cerebrospinal fluid (CSF) soluble TREM2 (sTREM2), and AD biomarkers. Methods From the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, 924 cognitively normal participants were enrolled in this cross-sectional analysis. We defined the following 11 HLCs: appropriate frequencies of coffee and tea consumption, sufficient frequencies of fish and fruit intake, non-social isolation, adequate sleep, regular physical activity, no depression, never smoking, non-hazardous drinking, and well-maintained blood pressure. We categorized participants according to the number of HLCs reported by participants into favorable, intermediate, and unfavorable lifestyle groups. Multiple linear regression was used to investigate the relationship among HLCs, CSF sTREM2, and AD biomarkers. Mediation effects were tested using a causal mediation analysis having 10,000 bootstrap iterations. Results Included subjects were with a mean age of 61.8 ± 10.2 years, of which 41.8% were female. Sufficient fish intake (β = −0.164, p = 0.017) and well-maintained blood pressure (β = −0.232, p = 0.006) were significantly correlated with lower CSF sTREM2 levels. A larger number of HLCs were associated with lower CSF T-tau (p = 0.001), P-tau (p = 0.012), and sTREM2 (p = 0.040) levels. CSF sTREM2 partially mediated the association between the number of HLCs and CSF tau pathology (mediating proportion T-tau: 22.4%; P-tau: 25.0%). Conclusions HLCs might impact the pathological processes of AD by regulating neuroinflammation.
A multi-modal and multi-stage region of interest-based fusion network convolutional neural network model to differentiate progressive mild cognitive impairment from stable mild cognitive impairment
Authors: Chen Zhenpeng , Qi Beier , Jing Bin , Dong Ruijuan , Chen Rong , Feng Pujie , Shou Yilu , Li Haiyun 
Published: November 2024

Background Accurately differentiating stable mild cognitive impairment (sMCI) from progressive MCI (pMCI) is clinically relevant, and identification of pMCI is crucial for timely treatment before it evolves into Alzheimer's disease (AD). Objective To construct a convolutional neural network (CNN) model to differentiate pMCI from sMCI integrating features from structural magnetic resonance imaging (sMRI) and positron emission tomography (PET) images. Methods We proposed a multi-modal and multi-stage region of interest (ROI)-based fusion network (m2ROI-FN) CNN model to differentiate pMCI from sMCI, adopting a multi-stage fusion strategy to integrate deep semantic features and multiple morphological metrics derived from ROIs of sMRI and PET images. Specifically, ten AD-related ROIs of each modality images were selected as patches inputting into 3D hierarchical CNNs. The deep semantic features extracted by the CNNs were fused through the multi-modal integration module and further combined with the multiple morphological metrics extracted by FreeSurfer. Finally, the multilayer perceptron classifier was utilized for subject-level MCI recognition. Results The proposed model achieved accuracy of 77.4% to differentiate pMCI from sMCI with 5-fold cross validation on the entire ADNI database. Further, ADNI-1&2 were formed into an independent sample for model training and validation, and ADNI-3&GO were formed into another independent sample for multi-center testing. The model achieved 73.2% accuracy in distinguishing pMCI and sMCI on ADNI-1&2 and 75% accuracy on ADNI-3&GO. Conclusions An effective m2ROI-FN model to distinguish pMCI from sMCI was proposed, which was capable of capturing distinctive features in ROIs of sMRI and PET images. The experimental results demonstrated that the model has the potential to differentiate pMCI from sMCI.