bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differences in cerebrospinal fluid and cerebral blood flow measurements by age, sex, and APOE4 status in older adults
Authors: Dong Yilei , Sakhare Ashwin , Stradford Joy , Monreal Teresa , Isenberg A. Lisette , Pa Judy 
Published: January 2025

AbstractBackgroundThe glymphatic system is important for clearing waste and transporting nutrients throughout the brain, but it’s still unknown how cerebrospinal fluid (CSF) and cerebral blood flow (CBF) contribute to Alzheimer’s Disease (AD). Phase‐contrast MRI (PC‐MRI) has been shown to reliably measure CSF and CBF at the cerebral aqueduct (CA) and second and third cervical vertebrae (C2‐C3) non‐invasively. The purpose of this study is to demonstrate CSF and CBF flow dynamics variations by age, sex, and APOE4 status in older adults.MethodSeventy‐nine healthy older adults (66.9±7.1 years old, 47 women) were recruited for this study from two larger clinical trials. All subjects received an MRI scan at baseline. CSF and CBF measurements were obtained using a 2D cine PC‐MRI pulse sequencing with retrospective cardiac gating. Measurements for CSF and CBF flow were taken at the CA, subarachnoid space (SS), and arteries between the C2‐C3. Correlation coefficients were calculated for age and CSF and CBF flow measurements, while mean and standard deviations of CSF and CBF flow measurements were calculated for sex and APOE4 status.ResultAge: For the CA, stroke volume (r=.23, p=.04) and total CBF (r=‐.26, p=.02) were significantly associated with age. For arteries, there was a non‐significant trend‐level association between age and arterial pulsatility index (r=.21, p=.06), arterial resistive index (r=.21, p=.06), and total stroke volume (r=‐.20, p=.08).Sex: Though non‐significant, there was a trend towards significance for women to have a greater SS fill peak than men (p=.07). In general, women had higher absolute values for CSF and CBF measurements, but they were largely not significant.APOE4 Status: There was no significant difference between APOE4 carriers and non‐carriers for any CSF and/or CBF measurements.ConclusionThis study shows that across age, sex, and APOE4 status, there are variations in CSF and CBF measurements for participants that may contribute to glymphatic clearance and AD.
The moderating effect of diet on the relationship between depression and Alzheimer’s disease‐related blood‐based biomarker
Authors: Shamsi Hilal Salim Al , Gardener Samantha L , Smith Stephanie Rainey , Sohrabi Hamid R. , Fernando Warnakulasuriya Mary Ann Dipika Binosha , Martins Ralph N 
Published: January 2025

AbstractBackgroundInterplay between diet, depression, and Alzheimer's disease (AD) shows promise as an important area of study for early intervention and therapy. Associations between both depression and diet and heightened AD risk underscore the need to examine the moderating effect of dietary patterns on the relationship between depression, and AD‐related blood‐based biomarkers.MethodData from cognitively unimpaired older adults (n=89; age ≥60 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were included. Participants completed a food frequency questionnaire, self‐report measures of depression, and had AD‐related blood‐based biomarker levels for phosphorylated tau (ptau181) 181, Aβ40, Aβ42, Neurofilament Light Chain (NfL), and Glial Fibrillary Acidic Protein (GFAP). Scores for two dietary patterns, 1) Mediterranean diet (MeDi), and 2) western diet were generated for each individual. Moderation and simple slope analyses were used to examine the interactions between dietary patterns, depression, and biomarker levels.ResultDepression was positively associated with NfL levels in males with lower than mean MeDi score adherence (β=3.759, SE=1.248, p=0.005). Depression was also positively associated with NfL levels in Apolipoprotein E (APOE) ε4 allele non‐carriers with lower than mean and mean MeDi score adherence (β=7.384, SE=1.972, p<0.001; β=3.797, SE=1.004, p<0.001, respectively).Moreover, depression was positively associated with Aβ40 levels in APOE ε4 allele non‐carriers with lower than mean and mean MeDi score adherence (β=16.837, SE=5.242, p=0.002; β=7.502, SE=2.669, p=0.005, respectively).No moderating effects of MeDi on the relationship between depression and levels of ptau181, Aβ42, and GFAP were observed. Furthermore, western diet had no moderating effect on the relationship between depression, and AD‐related blood‐based biomarkers.ConclusionThis study highlights MeDi adherence as a potential moderator of the relationship between mood and AD‐related blood‐based biomarker levels. These findings also emphasize the importance of gender‐ and genotype‐specific approaches to depression‐cognition‐diet research and highlight the need for further investigation.
DETECT‐AD ‐ Digital Evaluations and Technologies Enabling Clinical Translation for Alzheimer’s Disease: Results of amyloid screening methodologies in a simulated anti‐amyloid clinical trial using digital biomarkers as primary outcome measures
Authors: Kaye Jeffrey A , Mattek Nora , Mar Amanda B , Marcoe Jennifer , Hanna Elise J , Pierce Aimee , Shang Yanan , Wright Kirsten M , Wyatt Jonathan A , Schwartz Daniel , Gothard Sarah , Au‐Yeung Wan‐Tai M. , Steele Joel S. , Beattie Zachary T , Duff Kevin , Silbert Lisa C 
Published: January 2025

AbstractBackgroundWith the advent of anti‐amyloid therapies, identifying those with underlying amyloid burdens and detecting subsequent clinical effects of this AD pathology is critical. The DETECT‐AD study (ClinicalTrials.gov, NCT05385913) is a simulated secondary prevention anti‐amyloid clinical trial testing digital biomarkers as more sensitive and meaningful primary outcome measures. Clinically prodromal AD patients with estimable rates of AD progression based on Aβ PET status are enrolled as Aβ “positive” (higher amyloid burden) patients who predictably progress (as if receiving placebo) and Aβ “negative” patients progressing more slowly (representing the treatment group). Typical of current trials, participants are screened at entry to determine those with critical CNS amyloid burdens. Given the effort and cost of establishing AD phenotypes, efficient means for this screening are needed. Here we report to date the results of examining the screening process using blood‐based amyloid determinations for identifying florbetapir PET imaging‐based, amyloid status leading to enrollment of prodromal AD trial participants.MethodParticipants were initially screened by telephone using inclusion/exclusion criteria questionnaires. If passing this phase, participants underwent in‐person cognitive and neurological examinations and clinical blood tests; if passing this phase, an MRI/amyloid PET scan was performed; if passing this last step, the digital technologies were deployed in‐homes. The first 47 participants used this protocol. The subsequent 140 participants underwent a blood amyloid test (plasma Aβ42:40) first, and then the remaining procedures if intermediate or high risk for CNS amyloid (Aβ42:40 < 0.170).ResultA Consort Diagram shows the study results (Figure). As of 1/3/2024, 85/100 have been enrolled with mean(SD): follow‐up=59.4(21.3) weeks; age=78.2(6.5); 65% women; MoCA=25.0(2.5); PET SUVR=1.14(0.23), range: 0.806‐2.18. Without blood amyloid pre‐screening, 26% of participants were PET amyloid positive (SUVR≧1.11). With the blood amyloid screening, 52% were PET amyloid positive.ConclusionA simple telephone screen and blood amyloid test significantly improved the yield of amyloid PET positive participants in a simulated clinical trial, which can reduce costs, personnel effort, and participant burden and risk. Follow‐up will suggest how additional simple clinical, digital, and blood‐based biomarkers may further aid in identifying well‐defined target populations for clinical trials.
Safety of the CSF1R Inhibitor EI‐1071 in Human and Its Pharmacological Effects to Reduce Neuroinflammation and Improve Memory Function in a Mouse Model of Alzheimer’s Disease
Authors: Tamayanti Wahyu Dewi , Lin Jun Ru , Ariyanti Agnes Dwi , Chang Yenni , Cheng Haw Yuan , Huang Chia Wei , Ru Wu Cheng , Wang Chuan Yao , Hsieh Tsung Han , Lin Uni D , Pai Chi Yun , Tsai Jin‐Wu , Chen Hung‐Kai 
Published: January 2025

AbstractBackgroundMicroglial activation is one of the neuropathological hallmarks of Alzheimer’s disease (AD). Evidence suggest that chronic activation of microglia cause neuroinflammation and neuronal injuries, contributing to cognitive impairment. Therefore, modulation of microglial pathway like CSF‐1R represents an attractive therapeutic strategy. EI‐1071 (enrupatinib) is a brain‐penetrant CSF‐1R selective inhibitor that is in clinical development for AD treatment. Here we report the pharmacological effects of EI‐1071 on microglial modulation and neuronal functions in the 5xFAD model and the safety/tolerability demonstrated in a first‐in‐human trial.MethodIn animal studies, neurons in brains of 5xFAD mice were marked with EGFP via in utero electroporation. Mice with/without EI‐1071 treatment were assessed by behavioral studies including Novel Object Recognition (NOR) and Y‐maze followed by microscopic examination of Aβ plaques and GFP‐labelled neurons in brain slices. Changes in microglia and inflammatory biomarkers were analysed by immunofluorescent microscopy, RNA sequencing and/or quantitative PCR. A first‐in‐human phase 1 trial (NCT04238364) was conducted in healthy volunteers in compliance with the protocol approved by the regulatory authorities.ResultPharmacological inhibition of CSF‐1R by EI‐1071 induced significant changes in microglial homeostasis, neuroinflammation, and neuronal injuries. Those activated microglia surrounding amyloid plaques were greatly reduced accompanying with a declining tendency in amyloid plaques and neuronal death. Treatment of EI‐1071 did not eliminate all microglia. Homeostatic microglia were relatively well preserved as compared to the plaque‐associated microglia. Gene expression analysis revealed declines in microglial and proinflammatory genes and AD‐associated biomarkers including Iba1, Csf1r, Trem2 and Tyrobp. In addition, mice treated with EI‐1071 showed enhanced cognitive functions in NOR and Y maze tests.The phase 1 study enrolled 58 healthy volunteers into the single ascending dose and multiple ascending dose phases to assess the safety and tolerability of EI‐1071. All treatment emergent adverse events in the multiple dosing phase were grade 1, and were unrelated to EI‐1071 dosing.Conclusion1. EI‐1071 is effective in reducing activated microglia, neuroinflammation and neuronal injuries, resulting in a significant improvement of memory function in the 5xFAD model.2. EI‐1071 is well‐tolerated in a phase 1 clinical trial. The safety profile supports further investigation in patients with AD.
Prioritizing the Lived Experience: The Peer Reviewed Alzheimer’s Research Program
Authors: Fontaine Sarah N. , Brandt Katherine 
Published: January 2025

AbstractThe Congressionally Directed Medical Research Programs (CDMRP) originated in 1992 via a Congressional appropriation to foster novel approaches to biomedical research in response to the expressed needs of its stakeholders‐the American public, the military, and Congress. Currently there are 35 CDMRP programs each addressing a specific disease or condition.The Peer Reviewed Alzheimer’s Research Program (PRARP) began in 2011 and has a vision to mitigate the impact of Alzheimer’s and related dementias associated with military and diverse risks. To do this, the PRARP funds person‐centered research to address critical needs and improve quality of life for people living with Alzheimer’s diseases and related dementias.A CDMRP hallmark is the inclusion of people with lived experience at all levels. For the PRARP, this means inclusion as an equal voice and vote in setting the annual investment strategy and priority areas for a program, reviewing research applications, and making funding recommendations. They may be a person with a dementia diagnosis, family member, and/or care partner. This collaborative approach brings an important perspective and insight on the needs of the Alzheimer’s and dementia community and brings a sense of urgency to the entire process. The PRARP goes one step further and requires community collaboration in funded research projects. Any project proposing clinical research is required to have community collaboration throughout the design, execution, and dissemination of the research. This talk from the PRARP program manager and a PRARP lived experience peer‐reviewer will describe how people with lived experience are empowered to share their voice and are integrated throughout the PRARP’s processes and funded projects.
Participatory research involving people with neurodegenerative diseases and family caregivers: a systematic review
Authors: Daum Marcel , Ferra Fenia Gkolfo , Drewelow Eva , Walde Peggy , Gerullis Kai , Kilimann Ingo , Völlm Birgit , Teipel Stefan , Klein Olga A. 
Published: January 2025

AbstractBackgroundParticipatory research or patient and public involvement refer to the process of actively involving people with lived experience into the research process to improve its relevance, quality, and impact. In the PART project we aim to establish a sustainable structure to include underrepresented patient groups with neurodegenerative diseases into a patient advisory board for research. As one of our milestones, we conducted a systematic literature review with the aim of examining the impact of participatory research on people involved, such as those with cognitive impairment, caregivers, and researchers.ObjectiveTo explore the benefits, limitations and barriers of participatory research in the field of neurodegenerative diseases.MethodWe conducted a systematic literature review covering the databases PubMed, PsycINFO, CINAHL, Embase, Scopus, ClinicalTrials.gov, and Google Scholar, and added hand searches. The search strategy consisted of the terms “patients” AND “dementia” AND “participation” AND “impact” AND “research”. Based on the selection of relevant articles published between 2000 and 2022, we performed a quality assessment using the Mixed Methods Appraisal Tool (MMAT).ResultThe entire search yielded 1,994 articles, of which 1,169 remained after the removal of duplicates and were integrated into the screening process. Following a two‐step screening process and subsequent validation of a subset of 20% of the articles by a second reviewer, a set of 30 articles were selected for inclusion in the review. Current findings indicate that participatory research in the field of neurodegenerative diseases provides various advantages, such as empowering people with lived experience and enhancing researchers' understanding of those affected. Challenges included the extra time and effort required, as well as the difficulty of establishing a balanced relationship between researchers and co‐researchers.ConclusionThe number and quality of scientific articles regarding participatory research in the field of neurodegenerative diseases has been growing over the past two decades. The terminology used in reporting was frequently ambiguous, the description of participatory methods was often insufficient, and the impacts were frequently disregarded. Further research is required to address these issues and to investigate the impact of peer research in dementia studies.
Assessing the impact of fasting condition and storage time on plasma Amyloid‐β 42 and 40, pTau181, Nf‐L and GFAP measurements
Authors: Blasco‐Forniés Helena , Torres‐Torronteras Javier , Ortiz‐Romero Paula , Escalante Armand González , Minguillón Carolina , Anastasi Federica , Jiménez‐Moyano Esther , Suárez‐Calvet Marc , del Campo Marta 
Published: January 2025

AbstractBackgroundBlood biomarkers are essential in identifying Alzheimer's disease (AD) pathology. To ensure their clinical use, it is crucial to understand pre‐analytical factors such as fasting conditions and long‐term storage at ‐80°C. This study evaluates the effect of these factors on plasma biomarker concentrations for detecting AD pathology and neurodegeneration.MethodsPlasma biomarkers were measured in participants from the ALFA cohort using N4PE (Amyloid‐β [Aβ]40, Aβ42, Nf‐L, GFAP) and the pTau181 v2.1 advantage kits on Simoa HD‐X analyzer (Quanterix). To study the impact of fasting conditions, plasma samples from the same 16 participants in fasting and non‐fasting conditions were analysed. Aβ positivity in these participants was determined using CSF Aβ42/40 ratio. To assess long‐term storage at ‐80°C, we measured plasma biomarkers in samples stored at ‐80°C for 10 years (n=2339) and one year (n=381) from different participants. We compared differences on biomarker levels across groups, adjusting for age, sex and APOE‐ε4 genotype.ResultPlasma concentrations of Ab40 and Aβ42 were lower in samples obtained under fasting conditions than non‐fasting ones independently of their amyloid status. However, this effect was not observed in the plasma Aß42/40 ratio. No differences in the plasma concentration of GFAP, Nf‐L or pTau181 were detected between fasting and non‐fasting conditions. The performance of the different markers to discriminate amyloid positivity was similar across fasting conditions. We observed no differences on pTau181 levels between long‐ and short‐term storage at ‐80°C. However, we observed higher levels of Ab40, Ab42 and Ab42/40 (mean difference: 9.7%, 16.8% and 7.0%, respectively) and lower levels of GFAP (32.1%) and Nf‐L (13.9%) in samples stored for 10 years.ConclusionPlasma pTau181, a key predictor of amyloid pathology, remains unaffected by fasting and long‐term storage. However, fasting conditions influenced the measurements of Aβs, which was mitigated by considering the Aβ42/40 ratio. Notably, long‐term storage at ‐80°C may influence the concentration of Abs, GFAP, and Nf‐L, underpinning the need to consider storage time on plasma biomarker analyses. Future studies should include larger data sets for fasting conditions and evaluate additional factors that may influence the effect of storage time on biomarker levels.
A Cross‐Sectional Study to Evaluate the Impact of Dietary Patterns on Cognition in the Aging Urban Indian Population
Authors:   Amitha C M , Lingegodwa Abhishek Mensegere ,   Divya N M , Partha Ajith , Menon Meenakshi ,   Meghana R , Narayanasamy Rajitha , vishwanath Vindhya , HS Deva Kumar , Malo Palash K , Stezin Albert , Velavarajan Goutham , Arvind Prathima , Hameed Shafeeq K Shahul , HS Sunitha , Singh Sadhana , Mondal Banashree , Agrawal Deepashri , Sundarakumar Jonas S. , Issac Thomas Gregor 
Published: January 2025

AbstractBackgroundThe impact of the pattern of daily food consumption on cognition is a less explored area. This study aims to identify the impact of dietary patterns on the cognition of the elderly population, specifically comparing absolute vegetarians and omnivores.MethodIt is a cross‐sectional analysis of the aging urban Indian population of 1237 participants recruited from the ongoing Tata Longitudinal Study of Aging (TLSA). The information on diet was obtained using a diet questionnaire. Cognition was assessed using COGNITO (Computerized Assessment of Information Processing), ACE (Addenbrooke’s Cognitive Examination) which includes memory, attention, fluency, language, and visuospatial span. Chi‐square test and multiple linear regression analysis models were used for statistical analysis.ResultResults reveal a cohort of 824 absolute vegetarians and 413 omnivores, with the latter being comparatively younger, though literacy rates show no significant difference between the groups. There is a significant association between omnivores and in few cognitive domains such as visual attention (β: 0.451, p<0.001), and dual attention (β: 0.368, p<0.002).ConclusionThe presented data suggests a noteworthy association between mixed dietary patterns, and cognitive function among aging urban Indians. Absolute vegetarians are recommended to consume more proteins in their preferred food forms to have a positive impact on cognition. Incorporating dietary recommendations with a focus on promoting a balanced diet has implications for public health interventions.
Loneliness and Alzheimer’s disease: Testing associations using univariable and multivariable Mendelian randomisation models
Authors: Desai Roopal , Zuber Verena , John Amber , Marchant Natalie L , Charlesworth Georgina , Stott Joshua 
Published: January 2025

AbstractBackgroundSocial isolation, encompassing factors like living alone and limited social contact, is associated with increased risk of Alzheimer’s disease (AD). One theory is that loneliness, which is the negative psychological affect often associated with social isolation, mediates the relationship between social isolation and AD. Mendelian randomization (MR) approaches that have thus far been used to investigate causal relationships between loneliness and dementia risk have not supported results from observation studies. However, loneliness has shared genetic overlap with other traits which are independently associated with dementia. The presence of these pleiotropic risk factors may obscure the results of univariable MR analysis. Therefore, the aim of the current study was to better understand possible causal pathways between loneliness and dementia by including multiple pleiotropic risk factors, specifically educational attainment, alcohol dependence, neuroticism, obesity and smoking, in a multivariable Mendelian randomization (MVMR) analysis.MethodPublicly available genome‐wide association study data were used for the genetic instrument of loneliness and five pleiotropic risk factors and AD. A two‐sample univariable MR model was tested for loneliness and AD risk followed by a multivariable MR model to include the additional five pleiotropic risk factors.ResultUnivariable MR analysis indicated that genetic proxied risk of loneliness was not significantly associated with increased risk of AD (OR = 1.05, 95%CI: 0.72;3.65). In the multivariable model the estimate for loneliness (OR = 1.04, 95%CI:0.76;1.32) remained non‐significant. The pleiotropic paths of alcohol dependence (OR = 0.83, 95%CI:0.67;1.02), smoking (OR = 0.35, 95%CI:0.08;1.62), neuroticism (OR = 0.87, 95%CI:0.55;1.38), and education (OR = 0.56, 95%CI:0.21;1.54) were not significantly associated with increased risk for AD. However, higher body mass index (BMI) (OR = 0.41, 95%CI:0.19;0.87) appeared to reduce AD risk.ConclusionThe null findings reported here should be interpreted within the context of limitations inherent to MR models including, weak instrument bias and construct validity. Specifically, the loneliness measure may lack validity. Survivor bias may account for the unexpected direction of results for BMI. While our results suggest that most of the tested pathways were not significant, further research aimed at addressing the limitations of MR is needed to better understand the nuanced interplay between loneliness, pleiotropic risk factors, and AD risk.