bluuebunny/crossref_metadata_2025_split huggingface dataset:
Xanthohumol loaded self‐nano emulsifying drug delivery system: Harnessing neuroprotective effects in Alzheimer’s Disease management
Authors: Bashir Bushra , Singh Sachin Kumar , Gulati Monica , Vishwas Sukriti , Dua Kamal 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by the impairment of cognitive development and disruption of neurocognitive function. This neuropathological condition is marked by neurodegeneration, loss of neural tissue, and the formation of neurofibrillary tangles and Aβ plaques. Various studies reported the utilization of phytoconstituents like fisetin, quercetin, berberine, and xanthohumol for the treatment of AD. Among these phytoconstituents, XH is reported to have neuroprotective effects against AD by attenuating the levels of acetylcholinesterase (AChE) enzyme, accumulated amyloid β, oxidative stress, neuroinflammation, and mitochondrial dysfunction. In addition, XH also acts as senolytic, reducing the impact of cellular aging. Nevertheless, XH exhibits constrained solubility and encounters difficulty in traversing the blood‐brain barrier, thereby diminishing its efficacy in the target sites.MethodTo overcome these challenges, a self‐emulsifying drug delivery system (SNEDDS) for XH was devised, employing quality by design (QbD) based Box‐Behnken design (BBD). SNEDDS offers numerous advantages, encompassing increased drug loading, facile preparation, exceptional stability, as well as enhanced bioavailability and permeability across the blood‐brain barrier.ResultThe optimized XH‐loaded SNEDDS formulation exhibited droplet size, PDI, zeta potential, and drug loading as 40.23nm, 0.2, ‐15Mv, and 98% respectively. The formulation was found to be stable after six months in accelerated stability studies. The formulation underwent various pharmacodynamic studies. Pharmacodynamic studies assessed cognitive and motor functions in rats, revealing significant improvements in cognition with both low and high doses respectively. Additionally, the biochemical investigations revealed that the XH‐loaded SNEDDS effectively decreased the levels AChE enzyme, amyloid β, oxidative stress, and neuroinflammation.ConclusionThe study demonstrates that the utilization of XH‐loaded SNEDDS for addressing the challenges associated with AD treatment. The optimized XH‐loaded SNEDDS formulation exhibited favorable characteristics and stability, overcoming XH solubility constraints. The results suggest that the SNEDDS approach enhances the bioavailability and permeability of XH, highlighting its potential as a neuroprotective and senolytic agent for AD treatment.
Exploring the Interplay between Carotenoids, Lipid Oxidation, and Cognitive Impairment in Aging
Authors: Dias Irundika HK , Abdullah Sewa , Pickert Lena , Thimm Alexander , Abeysena Dumindri , Deelen Joris , Griffiths Helen R , Polidori Maria Cristina 
Published: January 2025

AbstractBackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, memory loss, and impaired daily functioning. As the global population ages, the prevalence of AD continues to rise, emphasising the urgent need for effective preventive and therapeutic strategies. Carotenoids, a group of naturally occurring pigments with antioxidant properties, have gained attention for their potential neuroprotective effects. Carotenoids interrupt the oxidative process by scavenging free radicals and quenching singlet oxygen, ultimately reducing lipid oxidation and preserving the integrity of lipids in biological systems. This project investigated the relationship between blood carotenoid levels, lipid oxidation and their impact on cognitive impairment.MethodSerum samples were collected from 49 healthy individuals (17 male, 32 female) who are 65 years or older. Serum carotenoids (Retinol, Lutein, Zeaxanthin, Lycopene, Alpha‐Tocopherol, β‐Carotene) were analysed by reversed phase HPLC method using methanol/acetonitrile/water gradient. Method validation was performed to establish linearity, sensitivity, recovery, and accuracy. Lipid oxidation products (oxysterols and oxidised phospholipids) were analysed using targeted mass spectrometry methods developed in our laboratory. Cognitive functions were measured using Montreal Cognitive Assessment, Trail Making Tests, letter fluency, category fluency and CogState.ResultHPLC assay for carotenoids assay showed a linear dynamic range (R2 > 0.94) of 0.01 µM‐20 µM for the six carotenoids that were tested. High intra‐ and inter‐day precision (CV < 9%) and high concentration accuracy (< 15% absolute error) were observed for the QC plasma samples. Correlation analyses did not show any relationship between cognitive status with serum carotenoids or oxysterols; 7‐ketocholesterol, 7β hydroxycholesterol and 25‐hydroxycholesterol and 27‐hydroxycholesterol). 27‐hydroxycholesterol was increased in individuals >80 years old.ConclusionOur data suggests some lipid oxidation products such as 27‐ hydroxycholesterol may increase with age. However, further analysis is needed to conclude how lipophilic carotenoids may associate with lipid oxidation and cognitive impairment.
Detection of Lamin A in mesenteric neurons: Accurate diagnostic method in patients with sporadic Alzheimer's Disease
Authors: Alberdi Laura Gil , Guerrero Carmen , Rebolledo Ana Belen 
Published: January 2025

AbstractBackgroundLamin A is barely expressed in human brain neurons or in murine models such as mice and rats. However, in Alheimer´s disease (AD) brains, neurons in the hippocampus and entorhinal cortex abnormally express lamina A from the initial stages of the disease, being a biomarker together with phosphorylated Tau of the nuclear pathology of AD.Constipation and mesenteric neuronal loss are related to aging and neurodegenerative diseases such as AD. It has been suggested that tau could be involved in enteric dysfunction, since it is expressed in enteric neurons and its presence has been reported in colon samples from AD patients. There is a bidirectional communication mechanism between the brain and the gastrointestinal system in which both organs influence the function of the other, suggesting that disease in either organ can affect the function of the other.The SPAM mouse model (expresses human tau with aggregating mutations S320F and P301S) in addition to presenting the neuronal cytoskeletal pathology of tau that manifests in AD (Braak V‐VI), expresses mutant phosphorylated tau in the cytoplasm of neurons of the myenteric plexus causing enteric neuronal death and functional impairment. SPAM tau mice also exhibit accumulation of phosphorylated tau in enteric neurons leading to significant neuronal loss and an early lethal intestinal phenotype.MethodParaffin sections obtained from colon biopsies from AD patients diagnosed post‐mortem as well as from healthy controls were processed for immunohistochemistry. The presence of the Lamin A in the nucleus of mesenteric neurons was analysed.ResultThe analysis by Immunohistochemistry showed the low nuclear expression of the biomarker Lamin A in the mesenteric neurons of the healthy samples and the overexpression of the biomarker in the colon samples of those diagnosed with AD.ConclusionThe results presented in this study show that Lamin A is clearly overexpressed in enteric neurons of patients with AD, unlike what happens in the enteric neurons of controls, which would indicate that neuronal nuclear pathology manifests in both systems, brain and colon, of patients with AD. This associated neurological implication suggests the possibility of using lamin A for therapeutic detection of AD.
Contrast‐agnostic deep‐learning‐based detection of perivascular spaces in magnetic resonance imaging
Authors: Díaz Mario , Fuchs Erelle , Mattern Hendrik , Behme Daniel , Duarte Roberto , Hernandez Maria del C. Valdes , Wardlaw Joanna M , Schreiber Stefanie , Trujillo Maria , Moyano Jose Bernal 
Published: January 2025

AbstractBackgroundTo date, all computerised perivascular spaces (PVS) quantification methods require case‐wise, imaging modality, or study‐specific parameter adjustments, and suffer from generalisability problems in clinical settings, and misdetection of other cerebral small vessel disease (CSVD) markers. We propose a deep learning‐based PVS detection method to overcome these issues. We compare our proposal on magnetic resonance imaging data of CSVD participants against the performance of the Frangi filter.MethodT1‐weighted (T1w) and T2‐weighted (T2w) neuroimaging data from 16 patients with severe CSVD were collected at the Hospital of the Otto‐von‐Guericke University Magdeburg. PVS across the entire brain tissue were manually segmented in T2w images by a medical student.We extended SynthSeg (https://surfer.nmr.mgh.harvard.edu/fswiki/SynthSeg) for PVS detection (Figure 1). PVS‐SynthSeg, our proposal, is based on a convolutional neural network and trained using synthetic data sampled from a generative model that relies on brain atlases as a conditioning factor, as well as domain randomisation. We incorporated tubular structures into such brain atlases to expand the model’s capabilities for the identification of PVS. This provides PVS‐SynthSeg with the ability to detect PVS in scans from diverse scanners and protocols without requiring additional fine‐tuning or parameter adjustments.We compared the precision and recall of PVS‐SynthSeg against that from the Frangi filter on both imaging modalities.ResultThe Frangi filter detected the majority of PVS in both T1w and T2w scans, albeit with high false positive rates–recall of approximately 80% and precision below 30% (Figure 2). PVS‐SynthSeg had more variability in recall but near‐one precision across both modalities, despite the presence of white matter hyperintensities (WMH).ConclusionWe propose a deep learning‐based PVS detection algorithm. In a small sample, PVS‐SynthSeg detected PVS in T1w and T2w scans better than the Frangi filter without additional adjustments, even in scans affected by motion artefacts or with WMH. These findings highlight the promise of PVS‐SynthSeg as a modular and effective PVS detection method, however larger cohort testing needs to be conducted. Better PVS quantification can help us shed light into the role of PVS in CSVD and Alzheimer’s disease.
Characterizing dementia risk in individuals with mild cognitive impairment using manifold learning, blood biomarkers, cognitive and imaging data
Authors: Casanova Ramon , Gaussoin Sarah A. , Lu Lingyi , Barnard Ryan , Duran Tugce , Bateman James R. , Lockhart Samuel N. , Deep Gagan , Hughes Timothy M. , Hayden Kathleen M. , Espeland Mark A. , Craft Suzanne 
Published: January 2025

AbstractBackgroundUniform manifold approximation and projection (UMAP) is a technique for dimension reduction and visualization of high‐dimensional (HD) data. Here, we apply UMAP to represent in two dimensions, data from members of the Wake Forest School of Medicine Alzheimer’s Disease Research Center (WFUSM‐ADRC) clinical cohort.MethodsWe examined baseline data from 542 WFUSM‐ADRC participants with mean age 70.1 years (range 54‐95 years), including 66% women and 18% Black self‐reported participants. A total of 195 participants were adjudicated with mild cognitive impairment(MCI), 67 with dementia and 280 were normal controls(NC) at baseline. Participants were further classified according to the stability of their cognitive status during 6.7 years of follow‐up with respect to baseline. We created a vector of 36 variables including cognitive tests, blood‐based biomarkers, MRI measures and age for each participant using baseline data. Based on UMAP, a 2D view of the data was created. Next, we fitted a nonlinear support vector machine with a Gaussian‐kernel and generated the boundary decision using data from participants classified at baseline as NC and dementia who kept the same status during their follow‐up. Data from individuals with MCI who remained stable, converted to dementia, or reverted to NC was provided to the classifier. The distance of each sample to the boundary was estimated. We evaluated this distance as a multimodal measure of AD dementia risk using a Wilcoxon test.ResultsThe classifier discriminated NC from dementia cases with an area under the curve of 96.3. The blue area in Figure 1 surrounded by the classifier’s boundary decision, we refer to as the “high‐risk zone”. Overall individuals with MCI falling inside the risk zone at baseline had significantly worse values of cognitive parameters (Verbal Fluency, AVLT, Digit Span, MoCA, Trails A &B), blood (GFAP, ptau181, NFL) and imaging biomarkers (AD Pattern Similarity scores, hippocampal and a temporal‐metaROI volume),(p < 0.001) than those individuals with MCI outside the high‐risk zone. Positive distances indicate the samples to be inside the zone. Differences in distances between the three MCIs groups were significant (p < 0.001).ConclusionsUMAP 2D projections have explanatory value to evaluate dementia risk in MCI.
Navigating Cultural Nuances: Understanding and Addressing Formal Care Utilization among Latino Family Caregivers of Older Adults with Dementia
Authors: Manzo Alma A , Britton Maggie , Segundo Joahana , Baker Zachary G 
Published: January 2025

AbstractBackgroundIn the United States, Latino older adults are 1.5x more likely to develop Alzheimer’s disease than non‐Latino White older adults. Latino Family Caregivers (LFC) maintain home care for longer periods of time but use formal care less. Latino cultural values such as familismo influence how LFC provide care, but many LFC report a lack of family assistance that might otherwise compensate for lower formal care usage.MethodsPhenomenological methodology was employed to understand LFC of people with dementia (n = 14). Participants were both female (n = 6) and male (n = 8) and interviews were conducted in both English (n = 8) and Spanish (n = 6). These semi‐structured interviews were analyzed via content analysis using NVivo 14 software. A primarily inductive approach was used to code the interviews; however, concepts were influenced by the Ottawa Decision Support Framework.ResultsTwo main categories were identified, (1) Reasons LFC might refrain from using formal care and (2) How/when LFC choose formal care. (1) Many LFC conceptualized formal care as untrustworthy (n = 10), unsafe (n = 8), expensive (n = 13), and found financial support elusive (n = 12). (2) However, LFC are likely to use at home formal care as disease severity progresses (n = 8). Discussing formal care decisions with family was common (n = 6), but consulting a doctor for advice was a majority preference (n = 11). LFC prized prior experience (n = 9) and “genuineness” in formal caregivers (n = 5). Lastly, although formal caregivers speaking Spanish was important (n = 8), embracing Latino culture was equally valuable (n = 8).ConclusionHealth care professionals (especially doctors) should consider cultural nuances when suggesting formal care to LFC’s. There are preconceived notions that LFC’s do not consider formal care, however if the formal caregiver is trustworthy, professional, and embraces Latino culture, LFC’s are likely to use formal care when the time is right. Future interventions should assist LFC’s in identifying professional and culturally competent formal caregivers and locating financial resources.
Association of sphingomyelin with Alzheimer’s pathology and cognition in non‐demented adults
Authors: Guo Fan , Sheng Ze‐Hu , Ma Lingzhi , Ou Ya‐nan , Zhao Qing‐Fei , Shan Tan Meng , Tan Lan 
Published: January 2025

AbstractBackgroundPlasma sphingolipids were discovered to identify memory impairment and Alzheimer’s disease (AD) risk. It has been reported to play a role in the pathological processes of neurodegeneration and neuroinflammation; however, its exact mechanism in AD has not yet been completely found.MethodA total of 476 non‐demented participants from Alzheimer’s Disease Neuroimaging Initiative were included. Multivariate cox regression was used to detect AD risk. Multiple linear regression and mixed effects modles were used to examine the sphingomyelins relationship with cerebrospinal fluid (CSF) AD biomarkers, white matter hyperintensities and cognitive. Causal mediation analysis was conducted through 10,000 bootstrapped iterations to explore the mediating effect of AD pathology on cognitive.ResultMultivariable Cox models showed that higher plasma sphingomyelin levels had lower risk of AD (HR = 0.9992; 95% CI, 0.9991 ‐ 0.9994; p < 0.004). Plasma sphingomyelin was positive correlated with RAVLT‐immediate scores, CSF Aβ42 levels, FDG‐PET, whole brain‐V, hippocampal‐V, fusiform‐V and EC‐THK. Meanwhile higher sphingomyelin is associated with lower CSF P‐tau and T‐tau levels, WMH and ventricular‐V. Higher plasma sphingomyelin can predict slower decrease of RAVLT‐immediate scores, FDG‐PET, whole brain‐V, fusiform‐V, MTL‐V, EC‐THK and increase of ventricular‐V. We found the association between sphingomyelin and verbal memory was partially mediated by levels of baseline CSF Aβ42, P‐tau and T‐tau; by FDG‐PET; and by hippocampal‐V. We found sphingomyelin interacted with cognitive diagnosis and APOEε4 status. The above results can be repeated and more pronounced in MCI, APOEε4 (+) groups.ConclusionThis study demonstrates higher plasma sphingomyelin was associated with lower AD risk and better verbal memory. Additionally, AD core pathology, along with brain metabolization and hippocampal atrophy, may mediate the association between plasma sphingomyelin and cognition. How sphingomyelin integrated within memory and AD pathways, suggests a novel possibility for identifying markers for early detection and potential avenues for effective therapeutic intervention in AD.
Associations of Circulating Platelet Endothelial Cell Adhesion Molecule‐1 Levels with Progression of Cerebral Small Vessel Disease, Cognitive Performance and Incident Dementia
Authors: Sim Ming Ann , Tan Eugene , Chan Siew‐Pang , Chai Yuek Ling , Chong Joyce R , Venketasubramanian Narayanaswamy , Tan Boon Yeow , Lai Mitchell Kim Peng , Hilal Saima , Chen Christopher 
Published: January 2025

AbstractBackgroundThe association between platelet endothelial cell adhesion molecule‐1 (PECAM‐1) with cerebral small vessel disease (CSVD) and cognition in non‐demented subjects remains un‐investigated.MethodA longitudinal, prospective cohort of subjects recruited from memory clinics was followed‐up for 5 years. Non‐demented subjects were included and classified as no cognitive impairment (NCI) or mild cognitive impairment (MCI). Annual neuropsychological assessments and 2‐yearly magnetic resonance imaging (MRI) scans were performed. The associations of baseline circulating plasma PECAM‐1 levels with neuroimaging markers of CSVD, cognitive decline (Montreal Cognitive Assessment [MoCA] scores and executive function Z‐scores), and conversion to dementia were evaluated.ResultOf 213 subjects (age 70.2±7.7 years, 51.2% male, 122 (57.3%) NCI, and 91 (42.7%) MCI), median PECAM‐1 levels were 0.790 [IQR 0.645‐0.955] ng/ml). Compared with the highest tertile, subjects within the lowest PECAM‐1 tertile had higher age‐related white matter changes scores (first tertile: β 1.50, 95% C.I. 0.23‐2.77, p=0.02) and cerebral microbleeds (first tertile: Adjusted risk ratio [ARR] 2.59, 95% C.I. 1.81‐3.72, p<0.0001). PECAM‐1 levels were not associated with baseline MOCA and executive function.Of the 204 participants with follow‐up data (median 60.0 [IQR 60.0‐60.0] months), 24 (11.8) had incident dementia. Compared with the highest tertile, subjects within the lower tertiles of PECAM‐1 were independently associated with higher risk of incident dementia (first tertile: Adjusted Hazard Ratio [AHR] 4.18, 95% C.I. 1.26‐13.93, p=0.020; second tertile: AHR 3.45, 95% C.I. 1.07‐11.14, p=0.038, Figure 1). The lowest PECAM‐1 tertile was associated with greater 4‐year progression of cerebral microbleeds (Incident Relative Risk [IRR] 2.44, 95% C.I. 1.20‐4.98, p=0.014), and decline in executive function (β ‐0.43, 95% C.I. ‐0.73, ‐0.14, p=0.004), and MoCA (β ‐1.32, 95% C.I. ‐2.30, ‐0.35, p=0.008) scores.ConclusionIn non‐demented subjects, lower circulating PECAM‐1 levels are associated with greater CSVD progression, cognitive decline, and incident dementia. PECAM‐1 may be a potential therapeutic target for CSVD and cognitive decline.
Alzheimer's disease subjects have smaller non‐jugular venous drainage system compared to cognitive normal population
Authors: Prado Keshet , Khasminsky Vadim , Keret Ophir , Beninger Felix , Goldberg Ilan , Auriel Eitan , Glik Amir 
Published: January 2025

AbstractBackgroundThe Internal Jugular Veins (IJVs) and the non‐jugular veins (NJVs) are two pathways responsible for intracranial blood drainage. The NJVs are usually the less prominent drainage system and have been demonstrated to become smaller during aging. This phenomenon may indicate less affective venues drainage and hence less CNS’s waste products clearance as we age.One of the pathological hallmarks in Alzheimer’s disease (AD) is amyloid betta42 (AB42) accumulation. AB42 accumulation may be the result of overproduction or clearance impairment. NJVs narrowing during aging may cause AB42 accumulation due to clearance impairment and hence plays a role in AD pathology.Our aim was to compare the venous cross‐sectional area (CSA) in AD vs. cognitive normal (CN) population.MethodCognitive impaired patients included AD and mild cognitive impairment (MCI) patients that were recruited prospectively as part of the DIASPORA Horizon‐2020 MesCobrad Project. All patients performed comprehensive neurocognitive evaluation and Brain MRI including Time‐of‐flight sequence for venous demonstration. Venous systems CSA were measured at the jugular foramen level and were done by senior neuroradiologist. CN were defined as subjects without CNS’s known pathology. CN Measurements were taken from a previous study of our group. T‐test was used to compare between groups.ResultA total of 39 Cognitive impaired patients and 20 CN were included in the study. Mean ages of 68 years (SD, 5.4) and 66 years (SD, 5.5), respectively. The CSA of the IJVs was similar between groups. However, NJVs CSA was significantly smaller in cognitive impaired patients (mean CSA=41.21 mm2 (SD,21.52) vs. CSA=54.5 mm2 (SD,27.3) P=0.045). Table 1.ConclusionNJVs are significantly smaller in cognitive impaired patients compared to CN population. NJVs narrowing in AD patients may cause impaired venous drainage hence causing AB42 accumulation in this population. New treatment options for AD patients may rise if larger studies replicate our findings.