bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential associations between plasma p‐tau181 and hippocampal subfield integrity across the Alzheimer’s disease diagnostic continuum
Authors: Rich Adea , Oh Hwamee 
Published: January 2025

AbstractBackgroundPlasma p‐tau181 is an increasingly established diagnostic marker for Alzheimer’s disease (AD); however, its precise relationship with brain tau pathology and the neural mechanisms underlying its association with cognitive impairment remain elusive. Our objective was to assess the association between plasma p‐tau181 and hippocampal (HC) subfield integrity and to investigate whether the subfields mediate the relationship between plasma p‐tau181 and cognition.MethodA total of 213 participants (57 cognitively normal, 109 mild cognitive impairment, and 47 AD) with plasma p‐tau181 measurements and high‐resolution T2‐weighted scans were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). HC subfield volume was measured at baseline using the Automatic Segmentation of Hippocampal Subfields (ASHS) software. Follow‐up HC subfield volume collected around one year was measured for eighty‐nine participants. A linear regression adjusted for age and sex evaluated the relationship between plasma p‐tau181 and HC subfields at baseline, as well as HC volume rate of change over one year. A mediation model assessed whether HC subfields mediate the association between plasma p‐tau181 and memory and executive functioning.ResultOur findings indicate that increasing levels of plasma p‐tau181(pg/mL) are associated with decreased volume in the left CA1 (β = ‐0.119, p = 0.019, Fig. 1a), right CA1 (β = ‐0.154, p = 0.005, Fig. 1b), left dentate gyrus (β = ‐0.120, p = 0.016, Fig. 1g), right dentate gyrus (β = ‐0.146, p = 0.005, Fig. 1h), and right entorhinal cortex (β = ‐0.091, p = 0.048, Fig. 1l). Moreover, these subfields partially mediate the relationship between plasma p‐tau181 and memory and executive functioning composite scores. Baseline plasma p‐tau181 did not predict longitudinal atrophy of the HC subfields across diagnostic groups.ConclusionOur study reveals consistent associations between plasma p‐tau181 levels and vulnerable HC subfields, including CA1, entorhinal cortex, and dentate gyrus, collectively implicated in normal aging and Alzheimer’s disease pathologies. Volumetric changes in CA1, dentate gyrus, and right entorhinal cortex were shown to underlie the association of plasma p‐tau181 with both memory and executive functioning. Together, our findings indicate that selective changes in HC subfield volume serve as a neural basis underlying the relationship between plasma p‐tau181 levels and cognitive impairment.
Development of a prototype ChLIA and a research‐use only ELISA for the detection of light chain neurofilament (NfL) in CSF
Authors: Zeplin Katharina , Niewand Julia , Franco Stephanie , Borchardt‐Lohölter Viola , Herbst Victor 
Published: January 2025

AbstractBackgroundIncreased levels of the light chain of neurofilament (NfL) in human cerebrospinal fluid indicate axonal damage. Their determination can support laboratory diagnosis and monitoring of neurological diseases associated with axonal damage. We developed a prototype chemiluminescence assay (ChLIA) and an enzyme‐linked immunoassay (ELISA, research use only) to detect NfL and report their analytical agreement with an established ELISA.MethodAgreement between the established NF‐light ELISA (UMANDiagnostics) and the Neurofilament Light (NfL) ELISA (EUROIMMUN) as well as the prototype NfL ChLIA (EUROIMMUN) was determined using 19 internal reference samples containing native NfL, with NfL levels distributed across the measurement range of the NF‐light ELISA. Possible bias between methods was estimated with Passing‐Bablok regression and Kolmogorov‐Smirnov CUSUM test.ResultComparison of NF‐light ELISA and Neurofilament Light (NfL) ELISA indicated a small proportional deviation with NF‐light ELISA values being higher than Neurofilament Light (NfL) ELISA values (regression: y = ‐63.9+0.97x, 95% CI intercept: [‐490.8, ‐79.67], CI slope: [0.89, 1.05], r = 0.08, CUSUM test p = 0.6). Comparison of Neurofilament Light (NfL) ELISA and prototype NfL ChLIA indicated a small shift with ChLIA values being higher than ELISA values, especially in the upper end of the measurement range (regression: y = 13.73+1.14x, CI intercept: [‐140.9, 97.05], CI slope: [1.07, 1.23], r = 0.98, CUSUM test p = 0.6).ConclusionThe results of analytical agreement between NfL levels determined by the ELISA and the prototype ChLIA in comparison to the established ELISA show promise regarding their performance characteristics. Being limited by the small sample size, these results will be followed up by a larger method comparison and validation study.
Peripheral parenchymal organ volume plays a role in neurodegenerative diseases: A Mendelian Randomization Study
Authors: An Dinghao , Xu Yun 
Published: January 2025

AbstractBackgroundSome studies have reported that neurodegenerative diseases can have different effects on the structure and function of peripheral organs, including organ volumes, and we wondered whether there is a genetic causal relationship between the two and whether changes in the volumes of parenchymal organs can affect the risk of developing neurodegenerative diseases.MethodOur SNP data were obtained from several different databases, including UKB and IEU OpenGWAS, and we analyzed them using bidirectional Mendelian randomization followed by comprehensive robustness analysis.ResultFor traditional genetic threshold: belly subcutaneous fat tissue volume can increase the risk of Alzheimer’s disease. Spleen volume can decrease the risk of amyotrophic lateral sclerosis. Pancreas volume may decrease the risk of amyotrophic lateral sclerosis. Dementia with Lewy bodies can decrease the risk of visceral fat tissue volume change while increasing the risk of spleen volume change. Alzheimer’s disease can decrease the risk of lung volume change, liver volume change, visceral fat tissue volume change, and pancreas volume change while increasing the risk of spleen volume change. For expanded genetic threshold: lung volume change can increase the risk of amyotrophic lateral sclerosis. Alzheimer’s disease can decrease the risk of belly subcutaneous fat tissue volume change, and visceral fat tissue volume change, and increase the risk of lung volume change.ConclusionWe found that some neurodegenerative diseases affect parenchymal organ volumes and that changes in the volumes of some organs increase the risk of developing neurodegenerative diseases, particularly the volumes of lung, spleen, pancreas, viscera fat tissue, and belly subcutaneous fat tissue. This may provide some new evidence and insights into the pathogenesis and comprehensive management of neurodegenerative diseases.
The Brain Tissue Properties Within the Cerebellum Play Role in Executive Functioning and Memory Performance in Healthy Older Adults
Authors: Moallemian Soodeh , Dapnée Chylinski , Van Egroo Maxime , Justinas Narbutas , Salmon Eric , Pierre Maquet , Collette Fabienne , Gilles Vandewalle , Phillips Christophe , Bastin Christine 
Published: January 2025

AbstractBackgroundCognitive function alterations are a feature of the cognitive aging process. Additionally, aging is marked by macro‐ and micro‐structural changes in the brain, such as gray matter (GM) atrophy, iron accumulation, and demyelination. This study explores the association between cognitive function and cooccurrence of brain micro‐ and macro‐structural changes in healthy older adults.MethodOne hundred and one participants (32% men, age range: 50‐69 years) were included in this study. All participants completed a cognitive assessment resulting in composite scores with mean = 0.00, s.d. = 0.99 for attention, executive functions, and memory. The preclinical Alzheimer’s cognitive composite (PACC5) was calculated for all participants (mean = 0.00, s.d. = 2.99). Quantitative magnetic resonance imaging (MRI) data were obtained using multiparametric mapping protocol. The association between cognitive composite scores and combinations of tissue properties was tested using multivariate generalized linear models (GLM) in Statistical Parametric Mapping (SPM) software.ResultVoxel‐wise multivariate GLM analyses revealed significant associations after family‐wise error rate correction between executive functions and the combination of macro‐ and micro‐structural changes within the cerebellum including right crus I and II, VII‐b (see Figure 1‐A). As illustrated in Figure 1, panels B and C, we also detected a correlation between memory and combined microstructural alterations in the in the left Cerebellum VIII‐b, as well as bilaterally within the cingulate gyrus and insula.ConclusionThese findings highlight the role of the cerebellum in cognition besides the complex relationship between cognition and brain micro‐ and macro‐structural properties in aging. As such, the involvement of the cerebellum in motor coordination and procedural memory may potentially influence executive functions
Driving Difficulty is an Important Mediator of the Impact of Visual Field Loss on Cognitive Impairment among Older Latinos
Authors: Zheng Alan C , McKean‐Cowdin Roberta , Torres Mina , Varma Rohit , Jiang Xuejuan 
Published: January 2025

AbstractBackgroundRecent studies have identified visual impairment as a potentially modifiable dementia risk factor. However, the underlying mechanism linking visual impairment and cognitive decline is still not fully understood. Additionally, there has been a dearth of research focusing on Latinos.MethodData were obtained from the Los Angeles Latino Eye Study (LALES), a population‐based longitudinal study of Mexican Americans aged 40 and above. The study performed comprehensive eye examination. Self‐reported vision‐related functioning was assessed using the National Eye Institute Visual Function Questionnaire (NEI‐VFQ‐25). Vision data were collected from the baseline visit, while the cognition data were obtained from the 8‐year follow up visit using the Cognitive Abilities Screening Instrument‐Short (CASI‐S) form. Multivariable linear regression models were used to assess the association with cognition. We explored the mediation effect of vision‐related health domains, such as driving difficulty, dependency, social function, and mental health. All analyses were conducted in R program.ResultA total of 3904 participants had valid vision and cognition data available for analyses. Visual acuity was not associated with CASI‐S score (P = 0.27) after adjusting for age, education level, and sex. However, greater visual field loss at baseline had a dose‐dependent association with lower CASI‐S score (P trend<0.001). Compared with individuals without visual field loss (mean deviation of ≥‐2 decibels [dB]), those with mild (‐6 dB ≤ to ←2dB), moderate (‐12dB ≤ to ←6dB), and severe (←12dB) loss demonstrated CASI‐S scores 0.45, 0.87, and 1.85 lower, respectively (Ps<0.001). With regards to individual vision disorders, such as cataracts, age‐related maculopathy, and diabetic retinopathy, no significant associations with CASI‐S scores were observed after adjusting for visual field loss, except for open‐angle glaucoma (β = ‐0.69, P = 0.022). Of the 10 vision‐related functioning indicators tested, driving difficulty had the largest mediatory effect. Notably, vision‐related driving difficulty was found to mediate 15.8% of the relationship between visual field loss and CASI‐S score, and social functioning accounted for 5.4%.ConclusionIn a cohort of community‐dwelling older Latinos, we found that visual field loss is associated with cognitive impairment. Vision‐related driving difficulty was identified as a more important mediator than social functioning, dependency, and mental health.
Association of retirement with MRI markers of vascular injury and neurodegeneration in a diverse cohort: Findings from KHANDLE and STAR
Authors: Chen Nancy X , Lor Yi , DeCarli Charles S. , Barnes Lisa L. , Gilsanz Paola , George Kristen M. , Maillard Pauline , Mayeda Elizabeth Rose , Glymour M. Maria , Whitmer Rachel A. 
Published: January 2025

AbstractBackgroundPrior research suggests that early retirement is associated with cognitive decline, but mechanisms are unknown. We investigated whether retirement is associated with MRI biomarkers of neurodegeneration and vascular injury in two diverse cohorts of adults ages 65+.MethodsThe Kaiser Healthy Aging and Diverse Life Experiences and the Study of Healthy Aging in African Americans are harmonized longitudinal cohorts of racially/ethnically diverse adults who are long‐term Kaiser Permanente Northern California members. We included adults 65+ years and categorized baseline retirement status (retired vs not retired). Regional brain volumes and white matter (WM) integrity were measured using 3T MRI among a random subset of the harmonized cohorts. Hippocampal volume (cm3), lateral ventricle volume (cm3), third ventricle volume (cm3), and log‐WM hyperintensities (log‐WMH) (cm3) were normalized on intracranial volume and age at scan. We also examined free water fraction (FW) and fractional anisotropy (FA) normalized at age at scan. Linear regression models estimated associations of retirement status with regional brain volumes and WM integrity. All models adjusted for gender, race/ethnicity, and education. Sensitivity analyses examined retirement categorized as 1) retired before age 65, 2) retired at age 65+, and 3) not retired.ResultsParticipants’ (N = 363) mean age at scan was 77.5 (SD = 6.3), 56% were women, 50% had < college education, 24% identified as non‐Latino White, 91% were retired, of whom 82% retired before age 65 (Table 1). Retirement was not associated with MRI, whereas timing of retirement was. Adults who retired at 65+ had smaller hippocampal volume (b = ‐0.17, 95%CI ‐0.35,0.00), compared to those who retired before 65 (Table 2). Adults who retired at 65+ also had larger ventricular volumes (lateral ventricle: b = 5.06, 95%CI 0.93,9.19; third ventricle: b = 0.16, 95%CI 0.05,0.27) and higher FW (b = 0.005, 95%CI 0.000,0.01) than those who retired before 65 (Table 2).ConclusionRetiring at 65+ appeared detrimental to late‐life brain health in this diverse cohort of older adults, contrary to the cognitive decline literature. Future studies should explore factors contributing to the impact of later retirement on late‐life brain health.
Relationship between perivascular spaces and white matter hyperintensities in Alzheimer’s disease
Authors: Tang Serena , Tosun Duygu 
Published: January 2025

AbstractBackgroundThere is increasing evidence that cerebrovascular and glymphatic‐related deficits may precede and influence AD pathology. In this study, we investigated the relationship between enlarged perivascular spaces (EPVS) as a measure of glymphatic clearance integrity and white matter hyperintensities (WMH) as a measure of cerebrovascular integrity.MethodParticipants from ADNI‐3 (N = 1026) who were diagnosed as cognitively unimpaired (CU) (n = 567), mild cognitively impaired (MCI) (n = 345), or AD dementia (n = 114) were included (Figure 2). Up to five visits (approximately one visit per year) were recorded for each participant. EPVS were segmented and quantified on 3T T1‐weighted images using a novel fully‐automated algorithm, while WMH were segmented on FLAIR images using the Lesion Segmentation Toolbox (Figure 1). Pairwise comparisons between EPVS and WMH metrics were tested using Mann‐Whitney U‐tests. A GLM was used to model the relationship between EPVS and WMH in each diagnostic group. LMMs were used to determine whether changes in WMH influenced EPVS changes between the groups. Age and sex were included as potential confounding factors, and data were transformed as needed.ResultIn the cross‐sectional analysis, the AD group had more EPVS count, volume, and WMH volume than the CU and MCI groups (Figure 2). A significant association was found between EPVS metrics and WMH volume (R‐squared = 0.4; p<0.001; Figure 3). MCI compared to CU presented a stronger association between EPVS count and WMH volume (p = 0.02). In the longitudinal analysis, EPVS count and volume significantly increased with time, however, no differences were found between groups (Figure 2). Changes in EPVS count were associated with changes in WMH volume, however, this association did not significantly differ between groups (Figure 2).ConclusionWe found that the association between measures of EPVS and WMH varies with different clinical stages of AD. This suggests that cerebrovascular and glymphatic‐related deficits may interact and exacerbate in all clinical stages with varying degrees and timing. Untangling the relationship between these pathophysiological changes and their influence on AD progression will further our understanding of the etiology of AD and highlight potential modifiable risk factors.
Association of Blood‐based DNA Methylation Markers with Cognition in Alzheimer’s Disease
Authors: Ng Kok Pin , Wang Ling , Dorajoo Rajkumar , Loh Marie , Ng Adeline Su Lyn , Hameed Shahul , Ting Simon Kang Seng , Kandiah Nagaendran , Liu Jianjun 
Published: January 2025

AbstractBackgroundDNA methylation is an epigenetic change characterized by the addition of methyl groups to DNA, typically in the cytosine‐ phosphate‐guanine (CpG) nucleotide base pairings. Given that DNA methylation alterations are shown to be associated with Alzheimer’s Disease (AD) pathology in autopsied brains, blood‐based DNA methylation changes are increasingly being studied as a potential peripheral biomarker for AD. However, the role of blood‐based DNA methylation changes as a marker of cognitive impairment in AD remains unclear. In this study, we aim to identify the blood‐based DNA methylation signatures that are associated with worse cognitive performance and brain atrophy in AD individuals.Methods277 AD patients of Chinese ethnicity were recruited from a tertiary memory clinic (National Neuroscience Institute, Singapore). All participants underwent the Montreal Cognitive Assessment (MoCA) test and blood collection. CpG probe methylation was measured using the Illumina Infinium MethylationEPIC BeadChip. A subset of participants (n = 218, 78.7%) underwent MRI brain scan and medial temporal lobe atrophy (MTA) score was measured visually. Regression analysis evaluated the associations of each methylation marker with MoCA and MTA scores, corrected for age, gender and years of education.ResultsWe identified two methylation markers (cg11103255 and cg10845701) to be associated with MoCA scores. Hypermethymation at the cg11103255 site was associated with lower MoCA scores (p = 2.86e‐07) while hypomethylation at the cg10845701 site was associated with lower MoCA scores (p = 8.18e‐07). Furthermore, hypomethylation at the cg10845701 site was associated with higher MTA scores. cg11103255 is mapped to the Microtubule Crosslinking Factor 1 (MTCL1) gene, a protein coding gene that enables microtubule binding activity. cg10845701 is mapped to the Solute Carrier Family 44 Member 5 (SLC44A5) gene, a protein coding gene that enables transmembrane transporter activity. While the role of MTCL1 gene on AD is not known, SLC44A5 was previously reported to be associated with brain atrophy in an AD GWAS.ConclusionOur findings demonstrate the potential role of blood‐based DNA methylation markers as measures of worse cognitive performance among AD. Further longitudinal studies in an independent cohort are needed to validate these findings.
Biological characterization and clinical application of tRF in cognitive impairment associated with white matter injury after chronic hypoperfusion
Authors: Fang Min 
Published: January 2025

AbstractBackgroundRecent studies have revealed that tRNA‐derived fragments(tRFs)are closely associated with the immunoinflammatory process of brain injury after stroke.MethodFirstly, 3 patients with WMI and the same number of healthy volunteers' peripheral blood in the control group were collected. EVS in the subjects' peripheral plasma was isolated and purified, and tRFs high‐throughput sequencing was performed. Subsequently, we verified significant differential expression of tRFs in sera from different oxygen glucose deprivation (OGD) cell lines and WMI patients. Next, possible tRF‐bound proteins were detected by RNA pull down combined with LC‐MS/MS targeted quantitative mass spectrometry. Finally, we collected serum samples from patients with WMI, including 20 each of cognitively normal and WMI‐associated cognitive impairment patients, analysed the relationship between significantly different tRFs and clinical indicators, and analysed the diagnostic efficacy of tRFs for WML‐associated cognitive impairment by ROC curves.Result1. The expression level of 3'Val‐TAC tRF was significantly higher in the serum of patients with WMI compared with controls; 2. 3'Val‐TAC tRF was not only significantly up‐regulated in OGD neuronal cells, but also was significantly highly expressed in the sera of patients with WMI; 3. 3'Val‐TAC tRF originated from mitochondrial tRNA, which belongs to tRF‐3b. A total of 86 proteins bound to the 3'Val‐TAC tRF compared to the negative control. Given the 87% peptide coverage of USP30 in the mass spectrometry results, it is highly suggestive that 3'Val‐TAC tRF is able to bind to USP30;4. The expression level of 3'Val‐TAC tRF was negatively correlated with the MoCA score (r = 0.376, P = 0.017). ROC curve analysis showed that 3'Val‐TAC tRF expression level had a high diagnostic value for WMI‐related cognitive impairment (AUC 0.835, P<0.001).Conclusion3'Val‐TAC tRF should be a small RNA that is highly expressed in WMI patients and induces WMI‐related cognitive impairment.
Investigation of amyloid‐beta 42 levels in human nasal discharge fluid from healthy and Alzheimer’s discovers diagnostic values
Authors: Jung Da Hae , Son Gowoon , Wang Shengmin , Lim Hyun Kook , Moon Cheil 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) therapy requires timely and accurate diagnosis for prompt drug intervention, emphasizing the need for a more accessible biomarker screening test. Previous studies identified higher expression of oligomeric Aβ in AD patients, however, the quantitative measurements of nasal Aβ42 levels of the full AD continuum remain unknown.MethodWe collected nasal discharge samples from 161 subjects who underwent neuropsychological battery tests and amyloid‐PET and nasal Aβ42 levels were measured via enzyme‐linked immunosorbent assay (ELISA).ResultOur results revealed that the second‐highest quartile (Q3) group of nasal Aβ42 had the majority of patients with AD diagnosis, and those in the Q3 group exhibited the most impaired cognitive function with a strong significance. Nasal Aβ42 levels were also associated with brain amyloid PET results and increased risk of developing AD.ConclusionOur findings suggest that nasal Aβ42 is a promising biomarker for AD diagnosis and risk assessment.