bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment effects of vitamin D3 and marine omega‐3 fatty acids on plasma ADRD biomarkers: Exploring sex and race differences
Authors: Vyas Chirag M. , Ostaszewski Beth L. , Anderson Amirah K. , Cook Nancy R. , Kang Jae H. , Gatchel Jennifer R. , Mischoulon David , Chang Grace , Reynolds Charles F. , Manson JoAnn E. , Selkoe Dennis J. , Okereke Olivia I. 
Published: January 2025

AbstractBackgroundThere is an urgent need to identify novel, accessible and affordable strategies to prevent cognitive decline and progression in the Alzheimer disease and related dementias (ADRD) continuum. Vitamin D3 and marine omega‐3 fatty acids (omega‐3s) supplements show promise for cognitive protection, with potential variations in their effects by sex or race. However, to date, no randomized clinical trials (RCTs) have tested their impact on emerging plasma‐based biomarkers with potential utility to predict ADRD pathogenesis.MethodsVitamin D and Omega‐3 Trial (VITAL) is a completed, nation‐wide, 2x2 factorial placebo‐controlled RCT testing vitamin D3 (2000 IU/d) and omega‐3s (1 g/d) for cancer and cardiovascular disease prevention. We included a Boston‐area sub‐cohort of 929 randomized VITAL participants who provided blood samples at baseline, 2‐year, and/or 4‐year follow‐up. Plasma ADRD biomarkers, including an N‐terminal tau fragment (NT1), amyloid‐β (Aβ)‐40, Aβ‐42, neurofilament‐light (NfL), and glial fibrillary acidic protein (GFAP), were measured. We used multivariable‐adjusted repeated measures models for data analysis; sex and race were pre‐specified effect modifiers.ResultsAmong 929 participants, the mean age was 65 years; 49.2% were females; 17.3% were from racial and/or ethnic minority backgrounds, including 8.2% Black adults. Neither vitamin D3 nor omega‐3s, compared to placebo, significantly reduced ADRD biomarkers overall across 4 years of treatment; however, there was a trend for reduction in Aβ‐40:Aβ‐42 ratio over 4 years for vitamin D3 versus placebo [percent difference (95% confidence interval [CI]): ‐1.2 (‐2.7, 0.3)]. Subgroup analyses uncorrected for multiple‐testing suggested interactions by sex and race. Vitamin D3 versus placebo resulted in a reduction in NT1 among males (‐2.7%) but not females (p‐interaction=0.08). Among Black participants, vitamin D3 versus placebo resulted in a 16% reduction in NfL levels [95% CI, ‐30.5% to 1.1%; p‐interaction=0.06], while omega‐3s versus placebo showed a 12.4% reduction in GFAP levels [95% CI, ‐21.5% to ‐2.2%; p‐interaction=0.049].ConclusionIn this RCT sub‐cohort of 929 older adults, neither vitamin D3 nor omega‐3s supplements significantly reduced selected plasma ADRD biomarkers over 4 years. We observed potential differences by sex and race in reductions of some ADRD biomarkers in response to these supplements which warrant further investigation in a larger sample.
Comparing regional and global diffusion MRI markers as biomarkers of VCID
Authors: Raghavan Sheelakumari , Reid Robert I. , Przybelski Scott A. , Kamykowski Michael G. , Lesnick Timothy G. , Graff‐Radford Jonathan , Lowe Val J. , Knopman David S. , Jack Clifford R. , Petersen Ronald C. , Vemuri Prashanthi 
Published: January 2025

AbstractBackgroundQuantifying white matter using diffusion MRI (dMRI) has been proposed for measuring early microstructural tissue changes due to cerebral small vessel disease and aid in quantifying vascular contributions to cognitive impairment and dementia (VCID). Our goal was to compare the usefulness of longitudinal white matter changes in the commonly available diffusion MRI measures for VCID prevention trials.MethodWe included 718 participants over 50 years of age (mean age: 71.1(9.6) years) from the Mayo Clinic Study of Aging, a population‐based sample, with at least two dMRI scans and structural imaging. We computed the commonly available single‐shell dMRI measures (fractional anisotropy, mean diffusivity, and two MarkVCID measures ‐ free water and peak‐width skeletonized mean diffusivity [PSMD]) at each time point. We tested for voxel‐wise associations between dMRI markers and vascular risk measured by cardiovascular metabolic condition (CMC) and observed a region‐specific dependance across all dMRI measures. Using both global and regional dMRI measures, we (i) examined the longitudinal association of dMRI measures with cognition and (ii) computed sample size estimates for a hypothetical clinical trial. We also included white matter hyperintensities (WMH) and our previously proposed composite vascular white matter score (combination of WMH and fractional anisotropy of the genu) as a comparison.ResultVascular risk was associated with all single shell dMRI measures in the genu of the corpus callosum, which we included as a regional dMRI marker for comparison (Figure 1). All dMRI markers correlated with cognitive performance longitudinally (Table 1) and had comparable sample size estimates required for hypothetical VCID clinical trials (Figure 2). Further, global free water and the composite vascular white matter score had the smallest sample size estimates.ConclusionAll commonly used dMRI markers had significant frontal lobe changes due to vascular risk. Both global and regional corpus callosum dMRI markers were sensitive to longitudinal cognitive decline, suggesting their utility in measuring the slowing down of VCID. The composite vascular white matter score, global free water, and WMH show promise as VCID biomarkers. Further work is needed to validate these markers on multiple populations.
Discovery of half‐curcumin‐based chemiluminescence probes and their applications in detecting quasi‐stable oxidized proteins
Authors: Ran Chongzhao , Yang Jun 
Published: January 2025

AbstractBackgroundOxidative stress, which refers to an imbalance between the production of reactive oxygen/nitrogen species (ROS/RNS) and the body's antioxidant defense mechanisms, is implicated in the pathogenesis of various chronic diseases by promoting cellular damage, inflammation, and dysfunction. Numerous methods have been reported for detecting ROS/RNS in vitro and in vivo; however, detecting methods for the secondary products of the ROS/RNS reactions, particularly quasi‐stable oxidized products, have been much less explored.MethodIn this report, we discovered that acetylacetone, a core moiety of curcumins, is a new scaffold for generating chemiluminescence in the presence of oxidants. With this new scaffold, we designed a series of half‐curcumins CRANAD‐Xs and demonstrated that CRANAD‐164 could be used to detect quasi‐stable oxidized proteins (QSOP) in patient serum samples and for in vivo imaging in animal models.ResultWe found that the QSOP levels were much higher in the disease serum samples, including Alzheimer’s disease, diabetes, multiple sclerosis, and pulmonary fibrosis, compared to the samples from healthy controls. Moreover, our results revealed that the sera chemiluminescence intensities were higher in aged healthy controls (60‐year old) compared to young healthy subjects (20‐year old), suggesting that CRANAD‐164 can be used to monitor the increase of QSOP in the course of aging.ConclusionOur results suggest that acetylacetone‐based chemiluminescence probes can potentially reflect the health status of a patient’s serum (blood) via in vitro diagnosis. In addition, the probes’ in vivo imaging capacity can be harnessed to facilitate fundamental studies and drug discovery of inflammatory diseases.
Neuropeptide Alterations in Alzheimer's Disease: A Meta‐Analysis of Cerebrospinal Fluid Concentrations
Authors: Muneer Muneeb Ahmad , Suresh Vinay , Bhonsale Aman Milind , Vasipalli Sonit Sai , Kumar Vignesh , Gowda Poorvikha , Javed Binish , Bardhan Mainak , Garg Ravindra Kumar , Malhotra Hardeep Singh 
Published: January 2025

AbstractBackgroundNeuropeptides are crucial proteins in the central nervous system, which significantly influence neurophysiological processes. This analysis explores cerebrospinal fluid alterations in Alzheimer's disease, offering insights to better understand the condition and explore novel diagnostic and therapeutic avenues.MethodWe systematically searched MEDLINE (PubMed), EMBASE, Cochrane, and Scopus using specific search strategies. Following PRISMA guidelines, our screening and extraction included studies that investigated neuropeptide concentrations in Alzheimer's patients' cerebrospinal fluid (CSF). Utilizing the 'meta' R package, particularly the 'metacont' tool, we analyzed mean concentration levels and standard differences via the random effects model. Data pooling utilized inverse variance weighting, with I² and tau² assessing heterogeneity. The restricted maximum−likelihood estimator and Q−profile informed tau² and its confidence interval. The primary outcome was the mean difference in CSF neuropeptide levels between Alzheimer's patients and controls, considering reported units separately.ResultIn our analysis of neuropeptides across diverse studies involving Alzheimer's Disease (AD) patients and controls, we observed distinct neurochemical alterations. Somatostatin showed a significant mean difference of ‐15.48 pg/mL (95% CI: ‐20.95 to ‐10.01, I² = 89%) in 9 studies (141 AD, 203 controls), and ‐8.05 pmol/L difference (95% CI: ‐13.35 to ‐2.76, I² = 0%) in 2 studies (44 AD, 57 controls). Neuropeptide Y (NPY) showed ‐8.83 pg/mL difference (95% CI: ‐19.81 to 2.16, I² = 65%) in 5 studies (76 AD, 95 controls), and ‐16.85 pmol/L difference (95% CI: ‐35.21 to 1.52, I² = 71%) in 3 studies (87 AD, 62 controls). Orexin exhibited a difference of 8.03 pg/mL (8 studies: 235 AD, 177 controls; ‐2.60; 18.67, I² = 27%, p‐value: 0.14). After excluding a study that significantly reduced heterogeneity, the adjusted result was 12.77 (95% CI: 1.16 ‐ 24.39, p‐value: 0.03). Substance P also showed a reduction in mean difference by ‐16.52 pg/mL (2 studies: 45 AD, 35 controls; ‐67.47; 34.42, I² = 87%) but was not statistically significant.ConclusionSomatostatin exhibited a consistent decrease in levels across studies, indicating potential relevance to AD pathophysiology. Additionally, orexin demonstrated a significant increase in levels in individuals diagnosed with Alzheimer's.
Markers of Interstitial Fluid Dynamics from Diffusion MRI Reveal Association with Amyloid Deposition in Cognitively Normal Older Adults
Authors: Chen Chang‐Le , Jin Hecheng , Schweitzer Noah , Minhas Davneet S , Villemagne Victor L , Yang Shaolin , Aizenstein Howard J , Wu Minjie 
Published: January 2025

AbstractBackgroundGlymphatic clearance dysfunction within the perivascular space has been implicated in Alzheimer's Disease (AD) pathology. Diffusion MRI‐based techniques such as DTI‐ALPS can quantify perivascular interstitial fluid (ISF) dynamics, yet their links with other early AD markers in the cognitively normal elderly population remain underexplored. Here, we investigated associations between DTI‐ALPS and cerebral β‐amyloid (Aβ) burden measured with Pittsburgh Compound B (PiB)‐PET. We also evaluated an augmented version of DTI‐ALPS to enhance sensitivity and better reflect the ISF diffusivity potentially associated with glymphatic function.MethodsDiffusion tensor images (DTI) and PiB‐PET images were collected from 40 cognitively normal older adults (age: 74.8 [5.8] years, sex: 18 males, mini‐mental state examination (MMSE): 28.8 [1.4], APOE‐e4%: 23%). Based on the DTI (acquired on a 3T MRI scanner with 12 diffusion directions, b‐value = 1000, and voxel size in 2 mm cubic), we estimated DTI‐ALPS index that evaluates the perivascular ISF movement along the medullary conduits and also developed an algorithm to generalize the definition of the traditional DTI‐ALPS by automatically localizing the periventricular space as the target area and calculating transverse tensor ratios as the primary measure (Figure 1). PiB‐PET analysis followed our previous validated approach, and the regional standardized uptake value ratios (SUVR) representing PiB retention relative to the cerebellar gray matter were averaged to determine global cerebral Aβ burden. Linear regression analysis was applied to investigate the relationship between DTI‐ALPS and global PiB‐PET SUVR.ResultsThe baseline model with the predictors of age, sex, MMSE and APOE4 status significantly explained the logarithmic global SUVR of PiB‐PET (Figure 2). When incorporating DTI‐ALPS indices, the baseline models were significantly improved (Likelihood‐ratio test: both p < 0.01); the explained variance increased by 15.3% and 19.3% by adding traditional and proposed augmented DTI‐ALPS indices, respectively. The models indicated that the DTI‐ALPS indices were significantly negatively associated with the global Aβ burden after adjusting the covariates (Figure 2).ConclusionWe observed that higher ISF diffusivity (likely better glymphatic clearance) corresponds to lower PiB‐PET retention (lower Aβ burden) in the cognitively normal older adults, suggesting the potential utility of ISF measures as a putative AD biomarker.
Sex Differences in Amyloid PET in a Large, Real‐Life Sample from the Imaging Dementia‐Evidence for Amyloid Scanning (IDEAS) Study
Authors: Raya Maison Abu , Zeltzer Ehud , Schonhaut Daniel R. , Allen Isabel Elaine , Carrillo Maria C. , Gatsonis Constantine , Hanna Lucy , Hillner Bruce E , Iaccarino Leo , March Andrew , Mundada Nidhi S , Mejía‐Perez Jhony Alejandro , Siegel Barry A. , Windon Charles , Whitmer Rachel A. , Joie Renaud La , Rabinovici Gil D. 
Published: January 2025

AbstractBackgroundPrevious studies on sex differences in amyloid burden have shown inconsistent findings. We examined the effect of sex on amyloid‐PET outcomes in a large, real‐world, cohort of individuals with cognitive impairment.MethodThe IDEAS study evaluated the clinical utility of amyloid‐PET in 18,295 Medicare beneficiaries age ≥65 years with MCI or dementia. All scans were visually interpreted as positive or negative at each site by a local radiologist or nuclear medicine physician. A subset of 10,361 scans were centrally processed and quantified in Centiloids. We used multivariate logistic regression to calculate odds ratios of amyloid‐PET positivity (based on visual read) for males and females, adjusting for demographic and clinical risk factors. We used linear regression to assess the association between sex and amyloid burden quantified in Centiloids.ResultOf 10,361 included individuals, 51% were females. Compared to males, females were slightly younger (75 versus 76 median age, p=0.008) and had higher rates of dementia (39.3% versus 35.2%, p<0.001). Rates of vascular risk factors were significantly higher in males than females, whereas females had significantly higher rates of history of depression and family history of AD. Females had higher rates of amyloid‐PET positivity than males (63% versus 59%, p<.001) and higher Centiloid values (median=48.7 versus 36.9, p<.01); see Figure 1 and Table 1 model 1. Sex differences remained significant in models adjusted for demographics and clinical risk factors (Table 1, models 2‐3). In an analysis that included only individuals with visually positive amyloid‐PET, females exhibited higher Centiloid values than males (Table 1 multivariable linear models). In amyloid‐positive individuals, we found a significant interaction between sex and age, with greatest sex differences in amyloid burden found in the youngest females (Figure 2A). We also found a significant interaction between sex and race, with greatest differences found in Black females vs. males (Figure 2B).ConclusionFemales with cognitive impairment exhibited a higher frequency of amyloid‐PET positivity and higher amyloid burden. Our findings shed light on sex‐specific biological and potential sociocultural differences in Alzheimer's disease pathology.
Mechanistic links of amyloid, atrophy, and cognition profiles for gait disturbance in Alzheimer's disease
Authors: Baek Min Seok , Seong Joon‐Kyung , Kim Sung‐Woo , Kim Dong Ho , Hong Jin Yong 
Published: January 2025

AbstractBackgroundThis study delves into the relationship between gait disturbances and the progression of Alzheimer's disease (AD), focusing on how these changes correlate with cognitive impairments and key neuropathological indicators.MethodWe prospectively enrolled 48 patients with AD dementia (ADD), 27 patients with prodromal AD (proAD), and 41 cognitively unimpaired (CU) individuals between January 2022 and May 2023. Participants underwent brain T1‐weighted MRI, 18F‐florbetaben PET, neuropsychiatric tests, and APOE genotyping, and quantified gait analysis was assessed using a 5.79‐m long pressure sensor embed walkway. To evaluate the relationships between gait parameters, cognitive scores, regional amyloid deposition, and regional cortical thickness, Pearson partial correlation coefficients were computed, adjusting for age, sex, education duration, and leg length. Path analysis was employed to test hypothetical models comprising cortical amyloid deposition, cortical thickness, cognition, and gait parameters. Our models hypothesized five main pathways: from amyloid deposition to cortical thickness, cognition, and gait parameters; and from cortical thickness to cognition and gait parameters.ResultAs AD progresses, a significant decline in velocity (p=0.0144 for comparing CU and proAD; p=0.0010 for comparing CU and ADD) and step length ( p=0.0033 for comparing CU and proAD; p= 0.0002 for comparing CU and ADD) was observed, indicative of a slower gait pace. The swing time percentage was reduced, and the double support time percentage was increased, showing a significant difference only in ADD patients ( p=0.0015 and p=0.0007 respectively). Gait variability, reflected in the standard deviations of step length and double support time, escalated with AD progression ( p=0.0173 and p=0.0143 for comparing CU and ADD, respectively) (Figure 1). Changes in gait pace, variability, and rhythm were found to be linked to neuroimaging markers of AD, including Aβ deposition in widespread areas and cortical atrophy in the inferior parietal and middle temporal gyri, precuneus, and insula (Figure 2). Path analysis revealed directed relationships between Aβ deposition and cognitive impairment, as well as cortical atrophy, collectively impacting gait disturbance in AD (Figure 3).ConclusionOur analysis indicates directed relationships between amyloid deposition and cognitive impairment, as well as cortical atrophy in these regions, collectively impacting gait disturbance in AD
Emerging role of serum biomarkers in neurodegenerative dementias in a diverse context
Authors: Arshad Faheem , Subramanian Sarada , Ramakrishnan Subasree , Alladi Suvarna 
Published: January 2025

AbstractBackgroundThe aetiology of Alzheimer’s Disease and Related dementias (ADRD) in a diverse context is complex, and clinical methods lack sensitivity and specificity due to overlapping symptoms. This underscores the need of novel serum biomarkers in diagnosis of dementia. Serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are non‐amyloid blood‐based biomarkers indicative of ongoing inflammatory and neurodegenerative process. We aimed to assess and validate their diagnostic value in patients with Alzheimer’s dementia (AD) and Frontotemporal dementia (FTD) spectrum disorders in the Indian context.MethodNinety‐nine participants recruited in the study underwent detailed neurocognitive assessment along with basic brain imaging. Quantitative determination of serum Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), total‐tau and ubiquitin C‐terminal hydrolase L1 (UCHL1) were assessed using Simoa platform following a 2‐step digital immunoassay method as per manufacturer’s instructions using HD‐X analyser. Healthy controls (n=29), and participants with AD (n=28) and FTD spectrum disorders (n=42) diagnosed as per standard criteria were recruited.ResultMean age of the participants and healthy controls was 61.26 years (10.31) and 55.69 years (8.97), respectively. GFAP and NfL were significantly higher in participants with dementia compared to healthy controls (p<0.001). Serum GFAP levels were higher in AD (p<0.001), while NfL levels were significantly elevated in AD and FTD compared to controls (p< 0.05). However, there was no difference in t‐tau and UCHL1 levels between dementia group and healthy controls. Higher biomarkers levels of serum GFAP, NfL, t‐tau and UCHL1 were significantly associated with increasing levels of severity of dementia (r=0.539, p=0.000; r=0.637, p=0.000; r=0.241, p=0.016; r=0.476, p=0.000; respectively).ConclusionLevels of GFAP and NfL in serum have an emerging role in differentiating ADRD (AD and FTD) from healthy controls. These biomarkers are valuable predictors of severity across the neurodegenerative dementias. Further prospective cohort studies are required to replicate these findings in a diverse context.
Coronary artery calcium and Alzheimer’s Disease biomarkers in cognitively unimpaired adults
Authors: Marcolini Sofia , Mondragon Jaime , Vliegenthart Rozemarijn , Teunissen Charlotte , Verberk Inge M.W. , Borra Ronald J.H. , Dierckx Rudi , Deyn Peter Paul De 
Published: January 2025

AbstractBackgroundAtherosclerosis, the hardening of arterial walls resulting in atherosclerotic plaques, is linked to cognitive dysfunction and an increased risk of cognitive decline. Findings on the impact of high coronary artery calcium (CAC), a subclinical atherosclerosis biomarker, on cognition remain inconsistent. Additionally, its effect on Alzheimer’s Disease (AD) biomarkers has not been previously analysed. This study explores differences in cognitive measures and AD biomarkers in cognitively unimpaired adults with absent or elevated evidence of CAC.Method285 cognitively unimpaired adults over fifty were recruited through the Lifelines database, a Dutch population‐based cohort study. Participants underwent non‐enhanced third‐generation dual‐source cardiac computerised tomography to derive total CAC using the Agatston score. They were categorized into two groups: participants with no evidence of CAC (all with a score=0; n=154) and participants with high CAC (with score>300; n=131). Subsequently, participants underwent a neuropsychological assessment and blood was sampled. Domain scores were created for memory, executive functioning, information processing, manual dexterity, and general cognition. Serum AD biomarkers (Aβ40, Aβ42, pTau181, NfL, GFAP) were analysed using a single‐molecule array assay technology. Group differences between the two groups were analysed using ANCOVA models adjusting for main confounders for normally distributed variables, and Mann–Whitney U otherwise.ResultAfter excluding participants with MMSE<25, 278 participants (68±9 years, 59% males) remained. CAC scores of participants in the high CAC group had median=667.5 and interquartile range=638.95. These participants, older and with more males, exhibited worse overall cognition [adjusted mean difference=‐0.28 (95% CI=‐0.48,‐0.08)], worse executive functioning [adjusted mean difference= ‐0.21(95% CI=‐0.38,‐0.04)] and higher pTau181 levels (z=‐2.50, p=0.01) compared to the group with absent CAC. No differences were found for all other determined AD biomarkers.ConclusionOur results suggest that individuals with high evidence of CAC might be at higher risk of cognitive decline, as evidenced by poorer cognitive function and elevated pTau181 levels. Ongoing investigations aim to validate early cognitive decline imaging markers, including advanced measures of cerebral perfusion and small vessel disease, and explore the relationship between cerebrovascular and AD markers in this population. Additionally, how these relationships vary at different levels of CAC severity is being examined.