bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Characteristics of Progressive Supranuclear Palsy Subtypes Defined by AT(N) CSF Biomarkers
Authors: Ishiguro Takanobu , Kasuga Kensaku , Tsukie Tamao , Onodera Osamu , Ikeuchi Takeshi 
Published: January 2025

AbstractBackgroundProgressive supranuclear palsy (PSP) may show concomitant neuropathological findings such as Alzheimer's disease (AD)‐related pathologies. Recent advances in CSF biomarkers enabled the estimation of neuropathological changes in brains in various neurodegenerative diseases. Clinical characteristic of subtypes of PSP defined by CSF biomarkers have not been well understood.MethodsNineteen PSP patients (11 males and 8 females, age at the examination: 72.9±7.9 years) who diagnosed by board‐certified neurologists were included in this study. They all met the criteria for 'probable,' 'possible,' or 'suggestive' PSP according to the MDS PSP criteria (2017). CSF AT(N) biomarkers including Aβ42 and Aβ42/40 ratio as A marker, p‐tau181 as T marker, and total tau [t‐tau] and neurofilament light chain [NfL]) as N marker were quantified. The positivity/negativity of each biomarker was determined based on the cutoff value defined in an independent cohort. PSP patients were classified into subgroup defined by AT(N) CSF biomarkers. Clinical characteristics were compared between the AD continuum (A+ profile) group and the non‐AD continuum (suspected non‐AD pathophysiology, SNAP) group. The activities of daily living (ADL) in PSP patients were evaluated using the Barthel Index.ResultsFourteen patients (74%) met the criteria for probable PSP‐Richardson syndrome. CSF AT(N) biomarker analysis revealed that the AD continuum pattern (A+ pattern) (AD [n=4] and, A+T‐N+ [n=8]) was observed in 12 PSP patients, and the SNAP pattern was observed in 7 PSP patients. The AD continuum group exhibited later onset (p=0.0009), lower MMSE scores (p=0.0177), and a higher frequency of axial rigidity (p=0.0379). CSF NfL showed a significant negative correlation with the Barthel Index in the entire PSP patients (r= ‐0.7281, p=0.001).ConclusionsDifferent clinical characteristics were observed in subgroups of PSP patients defined by AT(N) CSF biomarkers. PSP patients with the AD continuum had later onset and more impaired cognition than those without AD continuum. CSF NfL may be a valuable marker reflecting ADL in PSP patients.
Additive and interactive roles of alcohol use disorder and anxiety disorder on higher risk of Alzheimer’s disease and related dementias amongst hypertensive patients in high‐volume claims data: a retrospective study
Authors: Lundin Sori Kim , Hu Xinyue , Feng Jingna , Chen Yong , Schulz Paul E , Tao Cui 
Published: January 2025

AbstractBackgroundAlcohol use disorder (AUD) among elderly population is a strong risk factor for dementia. Anxiety disorder also poses a great toll on cognitive health and is commonly diagnosed among individuals with AUD. However, the additive and interactive roles of AUD‐anxiety disorder comorbidities on cognitive disorders such as Alzheimer’s disease and related dementias (ADRD) is poorly studied.Method6,390,826 individuals with hypertension were selected from US‐based Optum de‐identified Clinformatics® Data Mart. Baseline characteristics were compared between groups by the Chi‐square test for categorical variables and the Kruskal‐Wallis test for continuous variables. Kaplan‐Meier and adjusted cox proportional hazards (PH) model were used to study the additive and interactive associations of AUD and anxiety disorder in relation to the time from hypertension to ADRD.Result318,163 individuals with AUD and 6,072,663 without AUD were identified. Almost 70% of the AUD patients were male. Incidence of anxiety disorder, depression, substance use disorder, tobacco use, and COPD were significantly higher in AUD patients compared to non‐AUD patients (all P < 0.0001). In the Kaplan‐Meier plot, hypertensive individuals with AUD‐anxiety disorder comorbidity showed the highest cumulative hazards of ADRD, followed by those with anxiety disorder but no AUD. Individuals without AUD and anxiety disorder had the least cumulative hazards of ADRD. These four groups had a significant difference in their risk of ADRD (P < 0.0001). Using Cox PH analyses with additive terms, individuals with AUD comorbidity showed a 33% and 41% higher adjusted hazard ratio (aHR) of ADRD development than those without, among patients with and without anxiety disorder, respectively. Interactive terms of AUD and anxiety disorder were associated with 3% increase in aHR (P=0.012).ConclusionIn conclusion, our study found that AUD‐anxiety disorder comorbidities were associated with a higher risk of ADRDs from large‐volume claims data. We also found that the interaction of AUD‐anxiety disorders was linked to harmful effects against ADRD development. These results strongly suggest a critical need for combining medical and psychological efforts to fight dementia through integrative intervention on AUD and anxiety disorder.
The effect of social interaction intervention on cognitive functions among non‐demented older adults: A systematic review and meta‐analysis
Authors: Wei Chi chuan , Xie Ming‐Jia , Chuang Yi‐Fang 
Published: January 2025

AbstractBackgroundPrevious systemic reviews, predominantly including observational studies, have shown that participation in social activities is a protective factor against cognitive decline. However, this association is subject to potential reverse causality, creating a knowledge gap in our understanding of the effect of social interaction interventions on cognitive function. Therefore, this study aims to conduct a systematic review and meta‐analysis of randomized‐controlled trials to examine the effects of social interaction interventions on cognitive decline among non‐demented older adults.MethodThis systematic review was registered in PROSPERO (CRD42022367828), and we systematically searched six databases from inception to May 6, 2022, to identify relevant articles on the effects of activities with social interaction components on cognitive function in community‐dwelling non‐demented older adults over 60. Two independent reviewers performed study selection, data extraction, and bias assessment, and RevMan5.3 was used to conduct the meta‐analysis. Subgroup analysis was conducted to explore potential sources of heterogeneity and assess variation in intervention effects across subgroups.ResultWe included 11 studies for qualitative analysis and eight studies for the meta‐analysis. The result showed that social interaction intervention had a significant effect on executive function (SMD = 1.63; 95% CI, 0.55 to 2.70), but not attention (SMD = 0.09; 95% CI, ‐0.09 to 0.26) and memory (SMD = ‐0.03; 95% CI, ‐0.32 to 0.25). The subgroup analysis showed a greater cognitive benefit among normal older adults but not older adults with mild cognitive impairment. Additionally, when considering different social interaction modes, in‐person social interaction positively affected global cognition, while online interaction did not.ConclusionSocial interaction interventions have a limited impact on cognitive function in non‐demented older adults but showed potential effects on executive function. This finding offers insights for implementing social intervention in the community. Future efforts should focus on conducting more rigorous clinical trials to investigate the effects of different types of social interaction interventions on specific cognitive domains.
Five year trajectories of the mental and physical SF‐36 summary scores in men: results from the PREADViSE trial
Authors: Ding Xiuhua , Charnigo Richard , Schmitt Frederick A , Kryscio Richard J , Abner Erin L. 
Published: January 2025

AbstractBackgroundPrevious studies have shown that SF36 summary scores predict incident dementia. However, it is unclear whether SF36 summary scores follow different temporal trajectories. Thus, the goal of this study is to examine possible trajectories for SF36 summary scores.MethodA subset of 2,746 Prevention of Alzheimer’s Disease (AD) by Vitamin E and Selenium (PREADViSE) participants who completed SF‐36 assessments at annual visits was included in the current analysis. First, group‐based trajectory modeling (GBTM) was applied to fit SF‐36 Mental Component summary (MCS) scores and Physical Component Summary (PCS) scores. The final models were selected based on perceptions of interpretability and reproducibility with the assistance of the Bayesian information criterion (BIC). Then joint trajectory modeling was used to examine overlaps between trajectory groups based on MCS scores and trajectory groups based on PCS scores.ResultFour trajectories were identified for each of MCS and PCS, when examined separately. In terms of shape, MCS trajectories were described as stable (∼81.3% of subjects), curvilinear decline (∼ 4.3%), linear decline (∼ 11.2%) and slight increase (∼ 3.2%), while PCS trajectories were described as stable (∼48.7%) and slight decline (∼51.3% encompassing three groups). Joint trajectory modelling showed overlaps suggesting that MCS and PCS trajectories are not independent.ConclusionBoth MCS scores and PCS scores showed multiple trajectories over time; some were stable, and some exhibited decline. We were also able to estimate how many subjects belonged to each group and to quantify overlaps in group membership for MCS and PCS scores.
Longitudinal loneliness changes are associated with cognitive decline and brain structure alterations: evidence from the Whitehall II cohort study
Authors: Zhang Ye , Tatewaki Yasuko , Liu Yingxu , Tomita Naoki , Thyreau Benjamin , Taki Yasuyuki 
Published: January 2025

AbstractBackgroundLoneliness has been linked to cognitive decline and an elevated risk of Alzheimer’s disease (AD). Previous studies measured loneliness at a single point time, which may not accurately capture the longitudinal changes of different loneliness types (e.g., recover form loneliness; persistent loneliness) and their impact in the neuropathology of AD. This study investigates five‐year longitudinal changes of loneliness and their associations with cognitive function and brain structure alterations using data from the Whitehall II cohort study.MethodThis study included 5346 participants with mean age = 65 year (Female:26.68%) at baseline (2007‐2009). Loneliness was measured using one item form the Center for Epidemiologic Studies Depression Scale, and longitudinal loneliness changes were defined from two time points (2002‐2004; 2007‐2009). Linear mixed‐effect models were used to examine the association between different loneliness types and eight‐year changes of different cognitive domains (global cognition, reasoning, verbal fluency, and verbal memory). Robust linear regression models were employed to assess loneliness types and gray matter volumes (GMVs) in selected brain regions five‐year later (2012‐2012) using the Whitehall IIMRI substudy (N = 711).ResultWe defined four types of loneliness changes: “No loneliness”, “Transient loneliness”, “Incident loneliness” and “Persistent loneliness”. Compared to no loneliness, persistent loneliness was associated with decline in cognitive function (global cognition: b = ‐0.20, p<0.001; reasoning: b = ‐0.29, p<0.001; verbal memory: b = ‐0.11, p<0.007; verbal fluency: b = ‐0.15, p = 0.001;) after controlled for age, sex, education, and objective social isolation. Compared to no loneliness, persistent loneliness was associated with decreased GMVs in right posterior cingulate cortex (b = ‐0.17, pFDR‐corrected = 0.041); transient loneliness was associated with increased GMVs in rostral anterior cingulate cortex (b = ‐0.48, pFDR‐corrected = 0.025).ConclusionPersistent loneliness was associated with both longitudinal cognitive decline and decreased brain regions involved in emotional regulation, suggesting persistent loneliness feelings, no incident loneliness, could be a risk factor in the neuropathology of AD. Moreover, recovery from loneliness feeling (transient loneliness) could be protective in future brain structure alterations. Our study suggests that identifying participants has long‐term loneliness and developing strategies to overcome loneliness feeling could be important for AD prevention.
Heart rate fragmentation during a Stroop task reveals cognitively healthy individuals with pathological CSF amyloid/tau
Authors: Choy Elizabeth H. , Al‐Ezzi Abdulhakim , Buennagel David P , Nolty Anne , Fonteh Alfred N. , Kloner Robert A , Kleinman Michael T. , Arakaki Xianghong 
Published: January 2025

AbstractBackgroundStroop task is used to evaluate inhibition, a core executive function. Alpha Event‐Related Desynchronization (ERD) from analysis of electroencephalogram (EEG) during Stroop task reflects brain interference processing. We previously reported different relationships between heart rate variability (HRV) and alpha ERD during Stroop task. However, HRV proxied autonomic function can be confounded by increasing erratic rhythm with age, quantified by heart rate fragmentation (HRF). The knowledge of HRF is limited in a Cognitively Healthy (CH) cohort. To fill this gap, we studied these measurements in CH participants who underwent a Stroop task.MethodWe studied HRF in an established EEG dataset during Stroop task from CH participants when their CSF amyloid/tau ratio were normal (≥2.71, CH‐NATs) or pathological (<2.71, CH‐PATs). Heart rate fragmentation (HRF) was analyzed from 5‐minute electrocardiogram (ECG) during resting or task. HRF was classified into three categories: hard inflection point, soft inflection point, and non‐inflection. Hard inflection point represents an acceleration‐to‐deceleration (AD) in heart rate and vice versa (DA). Soft inflection point describes heart rate transitions from acceleration or deceleration‐to‐zero acceleration (AZ or DZ) and vice versa (ZA or ZD). Non inflection means heart rates are accelerating (NA), decelerating (ND), or no change (NZ).ResultWe previously reported that alpha ERD during incongruent trials were negatively correlated with heart rate (HR) in CH‐NATs but not in CH‐PATs (Figure 1). In CH‐NATs, there was a decrease in a subcategory of non‐inflection during task compared to resting (Figure 2A). We observed a significant increase in hard inflection points and a decrease in non‐inflections during Stroop task compared to resting in CH‐PATs (Figure 2B).ConclusionThese pilot results suggest: 1) from resting to task, CH‐PATs presented increase of HRF hard inflection points, which was not observed in CH‐NATs; 2) our previous analysis show that HR was negatively correlated with alpha ERD in CH‐NATs (higher HR related to more brain activation ‐ more negative alpha ERD), which was not observed in CH‐PATs. Although a larger sample size is needed, these results support a potential heart‐brain dysregulation using non‐invasive EEG and ECG in cognitively healthy individuals at higher risk of cognitive decline.
Classification of Apolipoprotein E ϵ4 Allele Carriers in Alzheimer Disease Patients and Healthy Controls using Event‐Related Potentials and Event‐Related Spectral Perturbation
Authors: Frassão Kauê O. , Filho Sandro M. S. , Pedroso Renata Valle , Nascimento Carla , Junior Henrique Pott , Cominetti Marcia Regina , Fraga Francisco J. 
Published: January 2025

AbstractBackgroundUnderstanding the genetic etiology of Alzheimer's disease (AD) has been a major focus of research in neurodegenerative diseases. Amid the three common allelic variants of the apolipoprotein E (APOE) gene in humans, called APOE ε2, ε3 and ε4, the ε4 allele is the most common genetic risk factor for late‐onset AD, being found in 20% of the world population.MethodWe used Event‐Related Potentials (ERP) and Event‐Related Spectral Perturbation (ERSP) as features for classification of apolipoprotein E ϵ4 (APOE ε4) allele carriers in AD patients and healthy controls. The study participants were 37 healthy older adults (9 APOE ε4 carriers) and 47 AD patients (15 APOE ε4 carriers), which underwent an auditory oddball task (with Target and Frequent trials) using an electroencephalographic (EEG) equipment with 21 channels. A leave‐one‐subject‐out (LOSO) cross‐validation approach was used to perform feature selection and classification with Support Vector Machine (SVM) classifiers.ResultAfter feature extraction and selection, we achieved a classification accuracy of 86,90% in the APOE ε4 carriers versus non‐carriers comparison (regardless diagnosis) and 85,71% in the Alzheimer disease patients versus healthy controls comparison (regardless APOE ε4 status). When combining the results of all participants we reached a global accuracy of 73,81% in the four‐class classification (Alzheimer disease patients carriers and non‐carriers, healthy elderly carriers and non‐carriers).ConclusionWe hope our work could help clinicians to make a more accurate and earlier AD diagnosis, considering the presence of the APOE ε4 allele.
Sex‐specific risk profiles associated with Alzheimer’s disease markers in cognitively unimpaired older adults
Authors: Touron Edelweiss , Wirth Miranka , Binette Alexa Pichet , Demnitz‐King Harriet , Collette Fabienne , Poisnel Géraldine , Vivien Denis , la Sayette Vincent De , Marchant Natalie L , Chételat Gael , Gonneaud Julie ,   the Medit‐Ageing Research Group
Published: January 2025

AbstractBackgroundDespite evidence that sex can modulate Alzheimer’s disease (AD) risk, whether risk factors are similarly related to AD markers in women and men remains largely unexplored. We aimed to assess how a combination of potentially modifiable risk factors are associated with cognitive and pathological markers of AD in older women and men.MethodWe included 135 cognitively unimpaired older adults (≥65 years old, 83 women; Table 1) from the Age‐Well trial (NCT02977819; baseline data) with multidomain assessments of modifiable risk factors, including cardiovascular (body mass index, systolic blood pressure, LDL cholesterol), lifestyle (complex mental activity throughout life, physical activity, diet), and psychological (quality of life, depressive and anxiety symptoms, rumination, worry). AD markers included the Preclinical Alzheimer Cognitive Composite‐5 (PACC‐5), a measure of global cognition sensitive to AD‐related decline, and multimodal neuroimaging and blood sampling providing measures of hippocampal volume (MRI), brain perfusion in temporo‐parietal regions, neocortical amyloid burden (PET) and p‐tau181 (plasma). Multivariate partial least squares analyses were used to assess relationships between combinations of risk factors and AD hallmarks (cognition, neurodegeneration, amyloid and tau) in women and men separately.ResultIn women, a combination of lower quality of life and complex mental activity throughout life and higher levels of anxiety and worry, was associated with lower PACC‐5 scores and higher p‐tau181 levels (p = .002, 60.5% of variance explained; Fig. 1). In men, two significant latent variables emerged. Lower systolic blood pressure, adherence to a Mediterranean diet and quality of life, and higher levels of anxiety and worry, were associated with higher hippocampal volume and lower brain perfusion in regions sensitive to AD (p = .022, 45.2% of the variance explained; Fig. 2A); while lower levels of quality of life and complex mental activity throughout life were associated with worse PACC‐5 scores and higher neocortical amyloid deposition and p‐tau181 levels (p = .023, 35.9% of the variance explained; Fig. 2B).ConclusionThese preliminary findings suggest that the modifiable factors that could influence AD markers may differ by sex in cognitively unimpaired older adults. Pending replication in larger and independent cohorts, these results highlight the need to consider sex specificities in prevention strategies.
How short peptides can disassemble ultra‐stable tau fibrils extracted from Alzheimer’s disease brain by a strain‐relief mechanism
Authors: Hou Ke , Ge Peng , Sawaya Michael R , Dolinsky Joshua L. , Yang Yuan , Jiang Yi Xiao , Lutter Liisa , Boyer David , Cheng Xinyi , Pi Justin , Zhang Jeffrey , Lu Jiahui , Yang Shixin , Yu Zhiheng , Feigon Juli , Eisenberg David S. 
Published: January 2025

AbstractBackgroundReducing fibrous aggregates of protein tau is a possible strategy for halting progression of Alzheimer’s disease (AD). Previously we found that in vitro the D‐peptide D‐TLKIVWC fragments tau fibrils from AD brains (AD‐tau) into benign segments, whereas its six‐residue analog D‐TLKIVW cannot. However, the underlying fragmentation mechanism remains unknown, preventing the further development of this type of drug candidate for AD.MethodTo understand the necessity of the cysteine residue of D‐TLKIVWC in fragmenting AD‐tau, we designed a series of peptides of sequence D‐TLKIVWX varying only at the seventh residue, X. To better understand the fragmentation process of AD‐tau, we conducted a time‐course dot blot and EM experiment. We determined the structures of D‐TLKIVWX amyloid‐like fibrils by atomic force microscopy and cryo‐electron microscopy. We studied the complexes of D‐TLKIVWX (X = I, S, R) with AD‐tau by cryo‐electron microscopy and confirmed the binding site between D‐TLKIVWX and Tau through NMR.ResultThese D‐TLKIVWX candidates showed various efficacies in fragmenting AD‐tau in vitro, in which X = Ile was the best performer. From electron microscopy, we discovered that D‐TLKIVWX peptides form amyloid‐like fibrils themselves, and from atomic force microscopy we learned that these fibrils have a right‐handed helical twist, in contrast to the left‐handed helical twist of AD‐tau. From cryo‐EM we learned that D‐TLKIVWX protofilaments bind to tau fibrils of opposing twist.ConclusionWe find that the amyloid‐like, fibril‐forming property of D‐TLKIVWX contributes to the fragmentation of AD‐tau fibrils. We propose the strain‐relief mechanism of fragmentation and believe the fragmentation of AD‐tau fibrils is driven by the release of torsion in D‐TLKIVWX protofilaments.